Successful pregnancy necessitates that the uterus is maintained in a relaxed, quiescent state for the majority of pregnancy, before being transformed to a contractile and excitable phenotype to facilitate parturition. There is now a substantial body of evidence highlighting key upstream regulators involved in this transformation. Despite our rapidly advancing knowledge of myometrial biology, the exact mechanisms that regulate parturition are not yet understood. Further work is necessary to define the complex interactions that form the key regulatory pathways controlling uterine quiescence, contractility, and the transition between the two states. Furthermore, new evidence continues to emerge implicating novel mechanisms that regulate uterine activity during normal and preterm birth. This review examines current evidence pertaining to key upstream regulators that have been implicated in human parturition over the past decades and surveys recent findings that are yet to be integrated into the paradigm of uterine regulation.