Parturition is a complex and involved process. Within the protected confines of the mother, the fetus grows rapidly for 37–42 weeks until the right combination of signals, stemming from both endocrine and mechanical stimulation, induces parturition, culminating in birth. Aberrations in these signals may lead to prematurity or stillbirth. Globally, nearly 13 million premature births and more than 3 million stillbirths occur each year1. Prematurity is a direct cause of 30% of all neonatal deaths, totaling more than 1 million annually, and often leads to developmental delays and serious long-term disabilities in those who survive. Many factors have been debated as causes of preterm birth (Fig. 1). Despite numerous clinical efforts to decrease the incidence of preterm birth, the major underlying mechanism of preterm labor remains unclear, as does the reason for the high incidence of preterm birth. Progesterone (P4), known as the ‘hormone of pregnancy,’is crucial for pregnancy success, as it supports embryo implantation and subsequent pregnancy maintenance. P4 fulfills these responsibilities by modulating uterine cell-specific proliferation and differentiation through differential gene expression in a manner dependent on the stage of pregnancy, such as implantation, decidualization (proliferation and differentiation of uterine stromal cells surrounding the implanting embryo) and placentation. Primary functions of P4 are to modulate the actions of estrogen; prepare the uterine lining for implantation and pregnancy maintenance; and, during pregnancy until parturition, confer quiescence of the uterine myometrium, the muscular layer of the uterine wall that contracts during labor. Given all of these functions, there has been a great deal of interest in examining whether P4 might have an effect on preterm delivery. Several recent clinical trials have tested P4 or its analogs for this condition. A randomized control study published in