Premature shortening of the cervix, or short cervix, is the most predictive risk factor for preterm birth. Results of clinical studies of interventions to prevent preterm birth have shown that identifying at-risk women on the basis of cervical length versus obstetric history alone improves the likelihood of timely interventions with cervical cerclage or progesterone supplementation, improving outcomes. Debate continues over the use of cerclage; however, results of a meta-analysis of randomized controlled trials provide evidence to support its use in women who have history of prior preterm birth and who develop short cervix before 24 weeks' gestation. Results of the recent PREGNANT trial, consistent with the earlier Fetal Medicine Foundation study, support the use of vaginal progesterone for prevention of preterm birth. In women identified by transvaginal ultrasound to have short cervix (10–20 mm) in midtrimester, daily vaginal progesterone gel reduced the risk of preterm birth before 33 weeks' gestation by 45% and before 28 weeks' gestation by 50%. Occurrence of any morbidity and mortality event also was significantly reduced by 43%, with a 61% reduction in the rate of respiratory distress syndrome in infants born to women receiving vaginal progesterone gel versus those receiving placebo. The safety profile of progesterone treatment in early pregnancy is well established, and studies of vaginal progesterone for prevention of preterm birth have identified no additional safety issues. Adverse events were comparable between women receiving progesterone and those receiving placebo. Recent guidelines issued by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend vaginal progesterone in women with no prior spontaneous preterm birth and cervical length of 20 mm or less at 24 weeks' gestation or earlier. Future studies will refine strategies for prevention of preterm birth to address other risk factors and determine the role of other interventions.