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Progesterone plays a central role in the mechanisms of parturition in many species. Despite remarkable advances in our understanding of this hormone's mechanism of action, its roles in human pregnancy maintenance and parturition are not fully appreciated. Proper scientific hypothesis testing of progestins to prevent preterm birth has been limited because of the issues that can plague interventional trials in obstetrics, including patient selection, choice of outcome and power. The largest studies enrolling patients with a history of prior preterm birth alone to prevent recurrence appear contradictory. In contrast, consistent evidence from one multinational trial and a secondary analysis of another suggests cervical length may serve to identify potential responders to this therapy. Finally, the safety of progestin administration is a legitimate concern and a meta-analysis justifies the need for further investigation of safety issues. This review presents recent findings regarding progestin therapy from both clinical and laboratory data and considers unresolved issues for use of these agents.