Sam Pickles awakens one morning on the small island where he works, and he feels the “Shifty Shadow” lurking. This is how he refers to strange sensations that he’ll occasionally feel when some sort of major shift in luck is about to occur; usually, it’s bad luck. Before he even starts his work day, his glove gets caught in the cogs of a machine, causing him to lose all of the fingers on his right hand. His wife Dolly eventually shows up at the hospital to visit him, and their children also show up: Rose, Ted, and Chub. After recovering, Sam returns home to the Eurythmic, a pub where the Pickles family has been living ever since Sam gambled away everything he owned. The pub is owned by Sam’s brother Joel, whose luck seems much more reliable than Sam’s. In the following weeks and months, Dolly can barely stand to look at her husband. Joel eventually gets Sam to go out and try living one-handed, encouraging him not to give up. The two of them go fishing on a beach one night, only for Joel to die of a heart attack.
Meanwhile, in another town, the Lamb family heads to the riverside to go prawn fishing. Staunch Christians Oriel and Lester Lamb have all six of their children in tow: three boys (Quick, Fish, and Lon) and three girls (Hattie, Elaine, and Red). As Oriel, the girls, and baby Lon stay on the beach and stoke the campfire, Lester, Quick, and Fish walk out into the river with a large net. It isn’t long before Fish is somehow pulled under the water so quickly that it takes a few moments for his father and brother to notice he’s submerged. Fish begins to drown, as he’s stuck under the net, and they can’t get it off him. After they drag him to shore and remove the net, Oriel tries to pummel the water out of her son’s body, praying aloud and demanding that God bring Fish back. To everyone’s delighted shock, Fish awakens. The Lambs drive him back into town to announce that a miracle has occurred, but Quick can tell that Fish isn’t the same as before. Fish is alive, but now he’s mentally impaired, with none of his original wit, cleverness, or personality.
In his last will and testament, Joel left Sam 2,000 pounds, as well as a large old house in Perth, where Joel had planned to retire. A proviso in Joel’s will prevents the house from being sold for the next 20 years, so the Pickles family moves to the house at Number One, Cloud Street. It’s very old and enormous, so it takes the Pickles family a while to adjust. Much to his family’s furious annoyance, Sam gambles his 2,000 pounds away almost immediately. To secure an income, Sam decides to rent out half of the house to another family. Rose hates the idea, but it’s already too late. Sam splits the backyard in half with a shoddy tin fence before welcoming the Lamb family into their home. The Lambs decided to move after realizing that Fish’s resurrection hadn’t been much of a miracle after all. They felt compelled to leave town because they no longer felt welcome, and they needed a fresh start.
The two families keep their distance from each other as the weeks and months wear on. Sam continues gambling at the racetrack with limited success, and Rose can’t decide whether to love him or hate him. Rose does hate Dolly, however, who’s been going out to pubs and getting drunk even more than usual. Fish’s brain damage has affected the Lamb family deeply; Lester and Quick blame themselves for the accident, and Fish doesn’t even seem able to perceive Oriel or acknowledge her existence at all. Fish behaves in a slow and childlike way, and it’s often painful for his family to watch. Nonetheless, they carry on. Oriel opens a general goods shop in the front of the house, which eventually comes to be known simply as Cloudstreet, along with the rest of the house. But her bustling attitude hides her self-doubt and uncertainty, and Lester shares these feelings. Ever since Fish’s accident, the Lambs have all but lost their faith in God, figuring that everything might be determined by random chance instead of a higher power with a plan.
Over the years, life goes on at Cloudstreet. Rose begins to develop an eating disorder. Quick still feels guilty over what happened to Fish, and he pins newspaper photos of miserable and suffering people on his wall, to remind himself of how lucky he is to be a survivor. One day, after Lester and Sam win a good deal of money at the horse races, the Lamb family visits the riverside to relax. Quick and Fish attempt to row home by themselves in a boat that Lester bought on impulse. This proves more difficult than expected, but in the dead of night the river and the world around them seem to turn into a sea of stars, as if they’re rowing through outer space. Fish is delighted, while Quick assumes he must be dreaming. At dawn, Lester is relieved to find the two of them sleeping in the boat, which ran aground near Cloudstreet. Soon afterwards, Oriel sets up a tent in the backyard and starts sleeping there every night, feeling unwelcome in the house and strangely alienated from her family.
Quick has trouble in school as his guilt and sadness threaten to overwhelm him. One night, he visits his mother at her second job at the Anzac club and tells her that he’s running away from home. The Lambs are saddened at his departure, but they carry on with their lives. Hattie Lamb starts seeing a young man named Geoffrey Birch, whom she plans to marry. Oriel successfully defeats her shop’s only competition in the neighborhood, Mr. G. M. Clay, only to guiltily discover that he’s also left town and left his wife and children behind. Desperate to feel that she’s doing the right thing, she opens her home to a lonely widow named Beryl Lee. Meanwhile, Rose Pickles finds a job at Bairds department store, where she works at a switchboard. She begins to eat again and becomes healthier, imagining a more independent life far away from her family and the strange old house. Fish continues his childlike behavior well into his teenage years, though he’s more subdued without Quick around.
Several years after he ran away from home, Quick now lives on his own as a young adult, working as a kangaroo hunter. As he hunts one night in a wheat field, a kick from a dying kangaroo knocks him out and sees a vision of Fish calling out to him and inviting Quick to follow. The man who hired Quick finds him lying in the field the next morning, and the man’s daughter Lucy tends to Quick’s wounds that night and seduces him. The two of them have a brief and unsuccessful relationship before Quick leaves town. He senses more and more signs and omens that seem to be calling him back home to Cloudstreet, but he runs from them. Eventually, while he’s working for his relative Earl, he starts glowing brightly, and Earl’s wife strongly suggests that they take him to Cloudstreet. By coincidence, they bring Quick home on the day of Hattie’s wedding to Geoffrey. Quick gradually stops glowing a week or two after returning to Cloudstreet.
A few more years go by. Beryl Lee decides to become a nun and leaves Cloudstreet to live at a convent, after admitting to Lester Lamb that she has feelings for him. Ted Pickles goes to live with a girl he got pregnant. Quick tries to adjust to life at Cloudstreet, but still feels uneasy and aimless. Rose meets a man named Toby Raven, who seems charming and cultured, and the two of them start dating. But after a few months, their relationship falls apart, and Rose finds herself crying by the river. Quick and Fish happen to pass by her in their fishing boat, and Quick offers to give her a ride. After Fish falls asleep in the boat, Quick and Rose start talking and quickly realize that they’re in love. They announce their intentions to marry each other the very next day, shocking both their families. The wedding takes place a few weeks later. After their honeymoon, Quick and Rose decide to start having a new house built for them, as Rose doesn’t like old places like Cloudstreet. They decide to live in a small flat until their house is finished. Quick becomes a constable and Rose soon becomes pregnant.
Quick and Rose soon run into serious complications. Sam senses the Shifty Shadow again one morning, and his intuition proves correct: in one day, Dolly falls down the stairs and breaks her leg, Ted has a fatal heart attack in a sauna, and Rose has a miscarriage. Rose becomes cold and withdrawn in the months following the miscarriage, falling back into her old undereating habits. Sam and Lester eventually convince her to visit Dolly, who’s been dangerously drunk and emotional ever since Ted’s death. During their conversation Dolly reveals that she was born of incest, and that her hatred of her own sisters has made her distrust other women. Rose and Dolly’s relationship improves after this conversation.
A sadistic killer begins murdering innocent people all throughout Perth at night, seemingly at random. Quick is rattled by his and the police force’s inability to stop the killer, and he and Rose move back into Cloudstreet to feel safer. They move into the old library room, which seems to be haunted. Rose becomes pregnant again. After several more gruesome murders, the killer is finally captured on the same day that Rose gives birth to her child, Harry. Quick is forced to realize that the killer is a man, just like him, when he finds the body of killer’s drowned son in the river. He tells Rose about his realization, and she comforts him and suggests that they go on a vacation. They soon make plans to drive to nowhere in particular for their vacation, and it’s assumed that they’ll finally move into their new house when they return.
Oriel arranges a massive dinner for both the Lambs and the Pickleses, wanting to hold onto Quick for one more night before he leaves her again. But during their short vacation (on which Rose and Quick reluctantly bring Fish), the couple discuss their future. Rose admits that, to her own surprise, she wants to keep living at Cloudstreet, as it truly feels like home to her now. Quick agrees, and they rush home the next morning to announce the news to the entire enormous household. Sam was considering selling the house, as 20 years have almost passed at this point, but he decides not to; as it turns out, everyone feels at home at Cloudstreet. To celebrate Quick and Rose staying, the Lambs and the Pickleses enjoy a large and loud picnic by the river, united as if they’re one huge family now. But suddenly, a delighted Fish plunges into the river before Quick can stop him. Fish seems to become more than a person as he drowns, seeing the whole history of the two families playing out in his mind in the moment before he dies. For that one moment, he’s become a man and reconnected with his former self, and he’s one with the river he always longed for.
With Fish gone, Oriel feels that she can finally move on. She and Dolly dismantle Oriel’s tent, indicating that she’ll be sleeping in the big old house at Number One, Cloudstreet from now on.