Much of our understanding and knowledge of human parturition has been blurred by conjecture and extrapolation. The limited available data on human parturition reflect the inability to directly experiment with pregnant human subjects. In spite of this obvious impediment and the scarcity of longitudinal data on fundamental physiological changes in human pregnancy, recent reports have generated a better understanding of the synchronous activities leading to labor. The purpose of this review was to organize, in an evidence-based format, the current understanding of maternal physiologic phenomena leading from uterine quiescence to uterine labor activity. Recent discoveries have prompted a revision of pre-existing classical theories on the initiation of parturition, such as the progesterone block theory or the prostaglandins stimulation of the uterotonic action of oxytocin. The presence in the circulation of extrahypothalamic corticotrophin-releasing hormone (CRH) produced by the placenta and myometrium is an inciting unique feature of primate pregnancy and a promising field for research. The concept of anatomical regionalization in labor promotion, including the cervical physiological inflammatory reaction, is also discussed in the review, especially in support of the strong link between inflammatory activation and onset of preterm labor. Understanding the intimate chain of events leading to parturition is critical, and elucidating the interplay of signals and processes that initiate normal labor may help us to understand the abnormal variant, spontaneous preterm labor, and devise efficacious interventions against it.