The cardiac conduction system initiates and propagates each heartbeat. Specialized conducting cells are a well-conserved phenomenon across vertebrate evolution, although mammalian and avian species harbor specific components unique to organisms with four-chamber hearts. Early histological studies in mammals provided evidence for a dominant pacemaker within the right atrium and clarified the existence of the specialized muscular axis responsible for atrioventricular conduction. Building on these seminal observations, contemporary genetic techniques in a multitude of model organisms has characterized the developmental ontogeny, gene regulatory networks, and functional importance of individual anatomical compartments within the cardiac conduction system. This review describes in detail the transcriptional and regulatory networks that act during cardiac conduction system development and homeostasis with a particular emphasis on networks implicated in human electrical variation by large genome-wide association studies. We conclude with a discussion of the clinical implications of these studies and describe some future directions.