The high prevalence, increasing frequency, and adverse outcomes for mothers and infants of preterm birth have led to heightened awareness of this public health concern. The causes of preterm birth are likely to be multifactorial, with genetic, infectious, nutritional, behavioral, and other environmental contributors. Because of important differences in the physiology of human pregnancy and that of nonprimate mammals, extrapolation of mechanisms from animal model systems to humans has had limited impact on the understanding of human prematurity. This review summarizes work from many groups that implicates important genetic contributions to human preterm birth. These efforts use epidemiological, classical genetic, and more recently, genomic science approaches to determine pregnancies at risk for preterm delivery and to facilitate an understanding of the substantial racial disparity in preterm birth. Data revealing racial and familial predispositions to prematurity, along with genetic polymorphisms conferring increased preterm birth, promise new insights into the understanding and treatment of this critical problem.