Our understanding of the pathophysiologic processes leading to preterm premature rupture of membranes (PPROM) has grown tremendously in recent years. Evidence suggests that there may be a genetic susceptibility to PPROM and that genetic and environmental elements are important cofactors in its development. A number of risk-based protocols have been proposed in an attempt to identify those women at highest risk for PPROM. While we have made advances in the area of predicting PPROM, treatments based on current risk-based systems have failed to distinguish a specific, effective preventive therapy for PPROM. The concept that genetic factors increase susceptibility or decrease resistance to disease has stimulated new work in the field of PPROM. Several maternal and fetal gene polymorphisms have been identified that are associated with an increased risk for PPROM. Patients with 'susceptible' genotypes may also have clinical risk factors for PPROM resulting in a synergistic increase in the risk for PPROM, a so-called gene-environment interaction. The concept that these gene-environment interactions represent new targets for our efforts to prevent PPROM is explored.