Progesterone plays a crucial role in maintaining pregnancy by promoting myometrial quiescence. The withdrawal of progesterone action signals the end of pregnancy and, in most mammalian species, this is achieved by a rapid fall in progesterone concentrations. However, in humans circulating progesterone concentrations remain high up to and during labour. Efforts to understand this phenomenon led to the 'functional progesterone withdrawal' hypothesis, whereby the pro-gestation actions of progesterone are withdrawn, despite circulating concentrations remaining elevated. The exact mechanism of functional progesterone withdrawal is still unclear and in recent years has been the focus of intense research. Emerging evidence now indicates that epigenetic regulation of progesterone receptor isoform expression may be the crucial mechanism by which functional progesterone withdrawal is achieved, effectively precipitating human labour despite high concentrations of circulating progesterone. This review examines current evidence that epigenetic mechanisms play a role in determining whether the pro-gestation or pro-contractile isoform of the progesterone receptor is expressed in the pregnant human uterus. We explore the mechanism by which these epigenetic modifications are achieved and, importantly, how these underlying epigenetic mechanisms are influenced by known regulators of uterine physiology, such as prostaglandins and oestrogens, in order to phenotypically transform the pregnant uterus and initiate labour.