We sought to review emerging data on the use of progesterone to prevent preterm birth (PTB). Using the terms "preterm or premature" and "progesterone" we queried the PubMed database, restricting our search to January 1, 2000, forward and selected randomized clinical trials (RCTs) and metaanalyses of RCTs that evaluated the use of progesterone for the prevention of PTB. We reviewed 238 abstracts and supplemented our review by a bibliographic search of selected reports. We focused on the pharmacologic aspects of progesterone and risk factor-specific outcomes. We identified a total of 17 relevant reports: 8 individual RCTs, 6 metaanalyses, and 3 national guidelines. Individual trials and metaanalyses support that synthetic intramuscular 17-alpha-hydroxyprogesterone effectively reduces the incidence of recurrent PTB in women with a history of spontaneous PTB. One trial found that vaginally administered natural progesterone reduced the risk of early PTB in women with a foreshortened cervix. The data are suggestive but inconclusive about: (1) the benefits of progesterone in the setting of arrested preterm labor; and (2) whether progesterone lowers perinatal morbidity or mortality. In some women, progesterone reduces the risk of PTB. Further study is required to identify appropriate candidates and optimal formulations. © 2009 Mosby, Inc. All rights reserved.