The following version of this book was used to create this guide: Keane, Mary Beth. Ask Again, Yes. Scribner, 2019.

Ask Again, Yes tells the story of two families’ intertwined lives in and around New York City, starting in 1973 and ending in the 2000s. The novel has four sections, which are organized by the characters' physical locations or their mental states. The novel uses a third person narrative stance to show the thoughts and feelings of many different characters.

The families, the Gleesons and the Stanhopes, live next door to each other in Gillam, a small town 20 minutes north of New York City. Both fathers, Francis Gleeson and Brian Stanhope, initially work as police officers in the NYPD. Bound by their jobs and the place they live, the families also become connected through tragedy and love. The Stanhope's only son, Peter, and the Gleeson's youngest daughter, Kate, grow up as best friends and eventually fall in love. Brain Stanhope's mentally ill wife, Anne Stanhope, shoots Francis Gleeson in the face one night. Although he survives, the shooting ends his law enforcement career. The bulk of the novel deals with the aftermath of the shooting and the characters' attempts to heal.

Anne Stanhope is committed to a mental hospital. Although no one understands her condition in the beginning of the novel, Anne eventually receives better treatment and begins to deal with her past in Ireland where she was molested as a little girl. Her husband quits his job with the NYPD and leaves Peter, his son, in Queens with his brother George. The Gleesons struggle through Francis Gleeson's long recovery. His wife, Lena Gleeson, cares for him, but this causes trouble in their marriage. Francis has an affair and Lena suffers from cancer. In the end, their marriage survives through the power of love.

Although Kate and Peter are estranged after the shooting, they reconnect in college, fall in love, get married and have children. Both, however, still struggle with the imprints the trauma of their childhood left on them. Peter becomes a police officer with the NYPD, but also develops an alcohol problem. Anne Stanhope is released from the mental hospital after serving six years there. She stalks her son and his family for much of the novel, but after Kate realizes she cannot tackle Peter's alcoholism alone, she asks Anne for help. Peter goes to rehab. The novel ends with the death of Brian Stanhope in the south from complications of diabetes. He has not had contact with his family for many years, but leaves them a sum of money and three photographs he used to keep in the hat he wore while working as a police officer. The photographs bring the two families together. Throughout the novel, Keane shows the power of love to heal.