I Know This Much Is True by Wally Lamb follows Dominick Birdsey on his quest to care for his schizophrenic identical twin, Thomas, and figure out their dysfunctional home life in the 1950s and 60s. Many of his revelations come from reading his maternal grandfather's self-serving memoir about life in Italy and Three Rivers, CT, in the early decades of the 20th century.

In 1990, in the Three Rivers Public Library, paranoid schizophrenic Thomas Birdsey amputates his right hand to end the growing war in Iraq. His identical twin, Dominick, the novel's anger-filled narrator, becomes his full-time advocate against a politically-motivated bureaucracy, in alliance with quirky caseworker Lisa Sheffer and psychologist, Dr. Rubina Patel, who soon begins treating Dominick's own anxieties over a broken marriage and a lifelong jealousy of Thomas for having been their mother's obvious favorite. As an adult, Dominick still hates his violent stepfather Ray and longs to know who his biological father is.

Much of the novel is devoted to flashbacks to the twins' difficult upbringing, spanning the Cold War and Vietnam War. While their mother is dying of cancer in 1987, she entrusts to Dominick her beloved Papa's memoir, "The History of Domenico Onofrio Tempesta, a Great Man from Humble Beginnings." As Dominick reads the long, self-serving text, spanning the early decades of the 20th century, he understands much about his mother's meek acceptance of her fate and his own volatile temper, but does not learn the secret of his paternity. Surprisingly, this comes from Ray, who mellows after losing a leg to diabetes, shares his own miserable early life, and reveals that their father is part African and part Wequonnoc Indian. Patel helps Dominick understand that Ma had shared this information with Thomas, knowing that he would accept it placidly, but had withheld it from Dominick, whom might have done himself harm. Her gift to Dominick had been the manuscript.

Thomas, like their beleaguered grandmother Ignazia, drowns himself to escape the evil world, freeing Dominick of much of his burden. He deals with being "untwinned." He and Dessa remarry and adopt the daughter of his post-divorce lover, Joy, who dies of AIDS. He reconciles with his stepfather in Ray's declining years, and turns the ancestral home into a refuge for abused women, named in Ma's memory. Dominick embraces his Wequonnoc heritage and finds peace and a measure of understanding.