The assumption that cardiac automaticity is a simple phenomenon has given way to recognition of a complex system derived from multiple components and their kinetic and dynamic interrelationships. We describe the gross anatomical and electrophysiological features of the pacemaker (P) cells in the sinus node, and explain their ability to depolarize during electrical diastole in terms of the ionic and molecular determinants of their currents: these include the If (f = funny) inward current, the putative initiator of phase 4 depolarization, activated not by depolarization of the membrane, as had been expected, but by hyperpolarization; the IK superfamily of delayed rectifier potassium currents; and the ICa,T and ICa,L calcium currents. Cloning of the molecular constructs of the individual currents has revealed four isoforms of the pacemaker channel, belonging to the hyperpolarization- activated, cyclic nucleotide (HCN)-gated family. The single most important modulator of sinus rate is the autonomic nervous system, comprising the sympathetic and parasympathetic neurons, the transduction pathways involved in autonomic signaling, and the biophysical targets of the autonomic channels, which are neurotransmitters. Although much investigation is still needed, it should ultimately be possible to replace or rejuvenate diseased pacemakers using techniques of molecular modification...