The natural pacemaker is the heart's natural rhythm generator. It employs pacemaker cells that produce electrical impulses, known as cardiac action potentials, which control the rate of contraction of the cardiac muscle, that is, the heart rate. In most humans, these cells are concentrated in the sinoatrial (SA) node, the primary pacemaker, which regulates the heart’s sinus rhythm.

Sometimes a secondary pacemaker sets the pace, if the SA node is damaged or if the electrical conduction system of the heart has problems. Cardiac arrhythmias can cause heart block, in which the contractions lose their rhythm. In humans, and sometimes in other animals, a mechanical device called an artificial pacemaker (or simply "pacemaker") may be used after damage to the body's intrinsic conduction system to produce these impulses synthetically.

The sinoatrial node (SA node) is the primary pacemaker of the heart. It is a region of cardiac muscle on the wall of the upper right atrium near to the superior vena cava entrance. The cells that make up the SA node are specialized cardiomyocytes known as pacemaker cells that can spontaneously generate cardiac action potentials. These signals are propagated through the heart's electrical conduction system. Only one percent of the heart muscle cells are conductive, the rest of the cardiomyocytes are contractile.

The SA node controls the rate of contraction for the entire heart muscle because its cells have the quickest rate of spontaneous depolarization, thus they initiate action potentials most quickly. The action potential generated by the SA node passes down the electrical conduction system of the heart, and depolarizes the other potential pacemaker cells at the AV node to initiate action potentials before these other cells have had a chance to generate their own spontaneous action potential, thus they contract and propagate electrical impulses to the pace set by the cells of the SA node. This is the normal conduction of electrical activity in the heart.

The pacemaker cells are connected to neighboring contractile cells via gap junctions, which enable them to locally depolarize adjacent cells. Gap junctions allow the passage of positive cations from the depolarization of the pacemaker cell to adjacent contractile cells. This starts the depolarization and eventual action potential in contractile cells. Having cardiomyocytes connected via gap junctions allow all contractile cells of the heart to act in a coordinated fashion and contract as a unit. All the while being in sync with the pacemaker cells; this is the property that allows the pacemaker cells to control contraction in all other cardiomyocytes.

Cells in the SA node spontaneously depolarize, ultimately resulting in contraction, approximately 100 times per minute. This native rate is constantly modified by the activity of sympathetic and parasympathetic nerve fibers via the autonomic nervous system, so that the average resting heart rate in adult humans is about 70 beats per minute.

Impulses from the sinus node reach the atrioventricular node which acts as the secondary pacemaker. The cells of the AV node normally discharge at about 40–60 beats per minute.

The atrioventricular node and the Bundle of His, a little further down, are located in the region separating the atria from the ventricles known as the atrioventricular junction. The Bundle of His transmits signals to the bundle branches, which send them on to the Purkinje fibers. These will also produce a spontaneous cardiac action potential at a rate of 30–40 beats per minute, so if the SA and AV node both fail to function, these cells can also become pacemakers but with a much lower rate of conduction than either the primary or secondary pacemakers.