The mechanisms involved in the initiation of human labor are largely unknown. Understanding the molecular pathways is fundamental in both the development of effective therapeutic strategies and intervention to prevent preterm labor. Prostaglandins are bioactive lipids and members of the eicosanoids family, derived from arachidonic acid, which act in a paracrine or autocrine manner and function via binding to specific G-protein-coupled receptors, activating intracellular signaling and gene transcription. Prostaglandins have a central role in the maintenance of pregnancy and initiation of labor, with the change from uterine quiescence to a contractile state facilitated by differential expression of prostaglandin receptors within the myometrium and fetal membranes. Clinical evidence for the key role of prostaglandins in human parturition is evident from their successful exploitation as exogenous agents for the induction of labor and the role of prostaglandin synthase inhibitors as a preventative therapy for preterm labor. This review aims to focus on prostaglandin synthesis and metabolism and how differential regulation of prostaglandins and their receptors in gestational tissues interact in the initiation of labor.