Salamanca Tree Hiddle is taking a trip with her grandparents from Euclid, Ohio to Lewiston, Idaho, to visit her mother's final resting place. Along the way, Salamanca, or Sal, tells her grandparents the story of her best friend, Phoebe Winterbottom, whose mother, like Sal's, unexpectedly decides to leave home. Sal meets Phoebe when Sal and her father leave their farm in Bybanks, Kentucky, to Euclid, Ohio, where Margaret Cadaver, whom Sal's father befriended after her mother's death, lives. Phoebe is a high-strung, prim, and wildly imaginative girl. She feels certain that some sinister connection exists between the morbidly-named Mrs. Cadaver, who is her next-door neighbor, the mysterious notes that keep appearing on her family's doorstep, and the strange boy, whom Phoebe dubs the lunatic, who appears at the house one day. Sal gradually becomes caught up in her friend's melodrama and finds herself engaged in a heady flirtation with a boy from school, Ben.
Sal intersperses Phoebe's story with memories of her mother, who was a loving, spontaneous, and gentle woman who could not shake off a deep sense of inadequacy next to her selfless husband. Phoebe's mother shares this sense of alienation. Her family routinely ignores her, and though she works assiduously as a mother and wife, she wonders at the smallness of her life. By this point in Sal's tale, she and her grandparents have reached South Dakota. They stop to swim in the Missouri River, where a snake bites Gram's leg. Sal and her grandfather rush Gram to the hospital, and although Gram recovers by the next morning, her health begins to falter after this point.
One day, Phoebe's mother disappears, leaving nary a word of explanation. Phoebe feels certain she has been kidnapped and begins an obsessive investigation for clues. Sal then retells the story of her own mother's disappearance. Sal, playing a good distance from the house, had fallen from the tree and broken her leg. Her mother, who was pregnant, carried Sal home and rushed her to the hospital. Later, she went into an early labor, lost the baby, and nearly lost her life. Overwhelmed with sadness, she insisted on taking a trip by herself to visit a cousin in Lewiston, Idaho. Sal and her grandparents are following the path Sal's mother took on her trip to Idaho.
Phoebe's family is growing more and more upset as the days go by, and Mr. Winterbottom, a reserved and stoic man, begins crying one day when Phoebe desperately insists that Mrs. Winterbottom loves her too much to leave without an explanation. Finally, Sal and Phoebe rush over to the police office to offer them the meager evidence they have collected. While there, Sal finds that the strange boy, the lunatic, who appeared on the porch earlier, is actually the police sergeant's son. Later that day, Sal discovers that Mrs. Cadaver, whom she resisted and resented due to her friendship with her father, suffered a great loss only a few years prior, when a car accident killed her husband and blinded her mother.
Sal and her grandparents take in Old Faithful, and Gram, whose breathing is troubled, revels in the splendor of the powerful geyser. When they leave Yellowstone National Park, Sal resumes her story, driven by a sense of urgency to finish it as soon as possible. Sal and Phoebe determine that the sergeant's son lives at a nearby college campus, and, convinced he holds the key to the mystery, take a bus to visit him. On campus, the two girls find the lunatic and Mrs. Winterbottom sitting on a bench, holding hands. Sal, overwhelmed, runs away as fast as her legs can carry her. She finds herself at a mental hospital, where, to her surprise, she finds Ben and his mother, who is a patient at the hospital. The two young people giddily share a delicious first kiss. Mrs. Winterbottom returns home a few days later and explains to her family that the lunatic is actually her illegitimate son, about whom she had always been afraid to tell her family for fear of letting them down. The Winterbottoms are shaken, but ready to listen to Mrs. Winterbottom. At the same time, Sal decides that she will make amends with Mrs. Cadaver and listen to her story. Mrs. Cadaver explains to Sal that she and Sal's mother became friends on the long bus trip from Ohio to Idaho, and that Mrs. Cadaver and Sal's father became friends because Mrs. Cadaver was the lone survivor of the accident that killed Sal's mother and was able to tell Sal's father about the last days and moments of Sal's mother's life.
Sal and her grandparents have reached Coeur D'Alene in northern Idaho, but Gramps and Sal must rush Gram, who is gravely ill, to a hospital. Gramps will not leave her side, but knowing that Sal feels she must visit her mother's grave on her birthday, which is the next day, allows Sal to drive down the steep, tortuous roads on her own. Sal makes the perilous drive in the dead of night, and finally stops at an outlook on a steep, switchbacked road where her mother's bus, more than a year prior, had tumbled off the road. Sal climbs down to inspect the wrecked, abandoned bus. When she returns to the car, a sheriff stands ready to arrest her, but when he hears her story, he drives Sal to her mother's grave and later back to Coeur D'Alene. Sal, already overwhelmed by tragedy, discovers that her grandmother has died.
Sal and her father later return to their farm in Bybanks, Kentucky and begin trying to rebuild their lives their without her mother. Sal, who has made peace with her mother's tragic death, looks forward to each day on the farm and to the upcoming visit of all her friends from Euclid, Ohio.