Preterm birth complicates 11% of all pregnancies in the United States and remains a leading cause of infant mortality and long-term neurological handicap. The majority of this morbidity and mortality is concentrated among the small subset of infants born before 32 weeks' gestational age and that have birth weights < 1500 g. Although the survival of these preterm infants has improved over the last 20 years, the rate of long-term handicap has not. Despite widespread use of preventive strategies, the rate of preterm birth is increasing. Therefore, the prevalence of long-term handicap attributed to preterm birth also is increasing. Considerable data implicate a clinically silent upper genital tract infection as a key component of the pathophysiology of a majority of early spontaneous preterm births, but a minority of preterm births that occur near term. This report reviews the current status of our understanding of the relationship between genital tract microbial infection and spontaneous preterm birth, the availability and usefulness of markers to identify women with such infections, and the results of recent prospective randomized clinical trials of antibiotic therapy to prevent preterm birth. Strengths and limitations of the trials are reviewed in relationship to their value for guidance in clinical management strategies and directions for future research are discussed.