The sinoatrial node (SAN) is the normal pacemaker of the heart. During a human lifetime it must initiate approximately 2 billion heartbeats and coordinate the cardiovascular response to our physiological and emotional demands. Disease of the SAN is common, and one of the leading indications for electronic pacemaker implantation. Advances in understanding the genetics and molecular mechanisms determining normal SAN function, and of the pathways controlling remodeling are revealing SAN disease to be heterogeneous. We review the contemporary concepts of SAN function, heart rate adaptation and SAN disease from the molecular level to clinical application.