"A Spool of Blue Thread" by Pulitzer-Prize-winning author, Anne Tyler, chronicles the loves and lives of three generations of the Whitshank family living in Baltimore, MD.

As the story opens the reader sees Abby and Red Whitshank receiving a call from their middle child, Denny, who has disappeared for many months. He tells his father on the phone that he is gay. When Red gasps in dismay, Denny hangs up on him. Abby tells him to call Denny back but they aren't able to because they don't have caller ID. Abby is furious and makes excuses for why Denny might have been gay all along. Red says he regrets marrying a social worker.

The reader learns that the Whitshank family are bound by many things, besides genetic material. They love to tell family stories. These stories include some of the more often repeated, such as how Abby and Red met, and how the Whitshanks of Boulton Street came to live in their great estate. In particular, Red, is fond of telling the story about how the Whitshanks came to live in the house that they still live in because he is able to paint his father as a man of great intellect and cunning. To the outsider, his father looks like an unethical con man.

Abby, who is in her early seventies, is beginning to show early signs of dementia. She often wanders off and can't find her way back, and she's taken to calling their dog, Brenda, by the name of a dog that they had back when the children were little. The reader learns that there are four children in the family: Amanda, Jeannie, Denny, and Stem. Stem wasn't really their biological son but had been taken in when his father, named Lonesome, died and the child's mother presumably couldn't be found. Abby is found wandering in the middle of a severe thunderstorm in the middle of the street with just her nightgown on.

Stem and his family determine that they need to move in to the family estate to help look after Abby and Red, who has had a heart attack. Red still owns and works at the family's construction business, and only a few days after his heart attack, insists on going back to the office. Stem, who works with him, takes him to work and looks after him. Stem and his wife, Nora, have three sons and a collie that they move in with. Nora is very capable and loving, but also practices a very strict form of Christianity that puts her at odds with the Whitshanks sometimes.

Denny, learning of his mother's problems and his father's heart attacks, comes to stay with them as well, which makes it very cramped quarters in their home. Stem tries to tell Denny to leave, and Denny resents it. He tells Stem that he's not the real child and that he doesn't have Whitshank blood. This sets up the conflict between the two, which will escalate later on in the novel.

Abby goes to a pottery class and, deciding to walk home, gets lost. The family search the roads and streets for her and find her seated on a neighbor's porch about a mile away. She goes to see a doctor who basically says that she does not have Alzheimer's but doesn't suggest that she has anything else wrong with her. However, two days later, she takes the dog for a walk (a dog that she continues to call by the wrong name) and is hit by a car when she runs into the road after the dog.

The family is devastated by Abby's loss. Red doesn't talk to anyone for days afterwards until it is determined that he hasn't turned his hearing aids on. The funeral is adequate for appearance's sake, but the real mourning happens when they return home and Abby is not there. Abby's best friend, Ree, and their neighbor stop by and she asks them all some very pointed questions about whether or not they should keep the house any longer. Red agrees to move into an apartment.

Meanwhile, Stem and Red are going through some of Abby's old papers and Stem finds an old contract that Abby had written. It discusses the identity of Stem's birthmother. To Stem's horror it is one of their neighbors, BJ Autry, who had lived in their neighborhood for decades and had never stepped forward to claim him. Stem is devastated. When he confronts Denny with the information, he realizes that Denny already knew. This infuriates him further.

Denny and Stem come to blows over who is going to stay in the home and who is going to move out. After their fight is over, they both decide that no one should live in the home. Meanwhile, Nora helps Red look for an apartment. He selects a grungy and dim looking little apartment and the girls are appalled. Red says that he is looking at the function of the apartment, not the social status.

The reader is then transported in time back to when Abby first met Red. Their courtship is examined and shows that while Abby was initially with another boy, she eventually chooses Red because, at heart, he is a good and decent person. Then, the reader is transported back even further to see how Junior (Red's father) and Linnie Mae (Red's mother) met. It was not really love at first sight, but more a case of mistaken identity. Junior had thought that Linnie was older than she was. After they'd had sex a few times he learns that she is only 13 and he is horrified. He tells her that she has to keep it secret or he could go to jail. The reader watches as the young couple are discovered and Junior is run out of town. Linnie's family don't speak to her for four years, even though she still lives on the farm with them.

The reader sees Linnie Mae turning 18 and leaving the farm to go to Baltimore to find Junior. She locates him and through a very rocky courtship end up together. Junior starts his own construction company and builds a house for a Mr. Brill, which Junior falls in love with. He manages to make the house look as if it is built in a crime ridden area of the city and Mr. Brill sells it to Junior cheaply.

Jumping forward to the future the reader sees the house being sold, the doors being closed, and Red moving into his apartment.