Preterm birth (PTB) is a major public health concern because of its high prevalence, associated mortality and morbidity, and expense from both short-term hospitalization and long-term disability. In 2002, 11.9% of U.S. births occurred before 37 weeks gestation. Epidemiologic studies have identified many demographic, behavioral, and medical characteristics associated with PTB risk. In addition, recent evidence indicates a role for genetic susceptibility. We reviewed 18 studies published before June 1, 2004, that examined associations between polymorphisms in the maternal or fetal genome and PTB risk. Studies of a polymorphism in tumor necrosis factor-α, a proinflammatory cytokine, showed the most consistent increase in the risk of PTB. Environmental factors such as infection, stress, and obesity, which activate inflammatory pathways, have been associated with PTB, suggesting that environmental and genetic risk factors might operate and interact through related pathways. This review highlights maternal and fetal genetic susceptibilities to PTB, the potential relationships with environmental risk factors, and the need for additional well-designed studies of this critical public health problem.