Preterm birth is a significant problem in the United States, contributing to neonatal morbidity and mortality. Progesterone is a hormone naturally produced by the corpus luteum and the placenta in early pregnancy and is essential for maintaining pregnancy. Clinicians and researchers have used this hormone in later gestation to try to prevent preterm birth. However, mechanisms of action, indications for use, dosing and administration have varied and are not fully understood. This article revisits two recent randomized controlled trials in which researchers investigated the effectiveness of vaginal progesterone suppositories and gel in the prevention of preterm birth among women who were at high risk for delivering prematurely.