The cardiac conduction system (CCS) is specialized tissue, which generates and propagates electrical impulses in the heart. The anatomy and function of each region of the CCS is ultimately responsible for the spatiotemporal regulation of atrial and ventricular muscle contraction during the cardiac cycle. In this way, the CCS orchestrates the rhythmic cardiac motion that provides a circulation of blood to the body. One part of the CCS, the sinoatrial node (SAN), is the pacemaker of the heart. It is subepicardially localized along the crista terminalis, a muscular ridge in the rear wall of the right atrium. The SAN exhibits high frequency spontaneous action potential (AP) firing and in this way sets the heart rate. The SAN is characterized by diastolic depolarization between APs (phase 4–responsible for spontaneous AP firing) and an AP with a slow upstroke (phase 0). This distinctive electrical activity is based on a unique expression profile of ion channels in the SAN. For example, ventricular myocytes have high expression levels of Kir2.1, NaV1.5 and KV4.3 that produce a stable resting potential (no diastolic depolarization), a steep AP upstroke, and a steep phase of early repolarization (phase 1) after the AP peak. In contrast, SAN myocytes lack these ion channels and instead have high expression levels of HCN and T-type Ca²⁺ channels, resulting in the characteristic electrical activity of the SAN. In this review, we summarize the molecular basis of SAN automaticity and discuss pathological changes of the ion channel profile in clinical and experimental settings.