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In a prologue, a young pioneer women drives a wagon West. In the main story, her great grandson, Martin Arrowsmith, is inspired by her pioneering spirit to become a medical student. As a young doctor, he desires to become a researcher, but his marriage to nurse Leora Tozer prevents his attaining the position he would like with Professor Max Gottlieb. Instead he goes with Lee to her small home town in Minnesota, where he becomes a country doctor. Despite the dull routine, Martin's brilliant mind keeps working and in a few years he discovers a serum to cure cows of Black Leg disease. His findings eventually lead to a position with Dr. Gottlieb at the McGurk Institute in New York. Lee has had a miscarriage and devotes herself to Martin, although his research keeps him away for long hours. When Gustav Sondelius, a scientist and friend of Martin and Dr. Gottlieb's announces that plague is raging in the West Indies, Martin goes to test a new serum he has developed, promising Gottlieb that he will only innoculate half of his patients in order to test his results scientifically. Lee accompanies him, despite Martin's concerns. On the island, the white citizens will not submit to his tests, but the natives, led by a Howard University-educated black doctor named Oliver Marchand, willingly cooperate with him. Martin must go to one of the other islands, leaving Lee alone. There he meets plantation-owner Lanyon and his daughter Joyce, who help him. After Sondelius dies from plague, Martin and Joyce go to bed together. The next morning he recives a call from Marchand, who has returned to the main island. When Marchand collapses from the plague, Martin hurries home, worried that Lee may also be infected. When he returns, she is dead, having contracted the disease through a cigarette carelessly placed in Martin's lab. Distraught, Martin drunkenly allows everyone to have the serum, destroying his scientific research. When he returns to New York, Gottlieb suffers a stroke and Martin decides to go with his co-worker, Terry Wickett, to Vermont to open a lab. Joyce offers her friendship to him, but he leaves, wanting to re-new his committment to pure research with Lee spiritually with him.