SummaryCardiac alternans refers to a condition in which there is a periodic beat‐to‐beat oscillation in electrical activity and the strength of cardiac muscle contraction at a constant heart rate. Clinically, cardiac alternans occurs in settings that are typical for cardiac arrhythmias and has been causally linked to these conditions. At the cellular level, alternans is defined as beat‐to‐beat alternations in contraction amplitude (mechanical alternans), action potential duration (APD; electrical or APD alternans) and Ca2+ transient amplitude (Ca2+ alternans). The cause of alternans is multifactorial; however, alternans always originate from disturbances of the bidirectional coupling between membrane voltage (Vm) and intracellular calcium ([Ca2+]i). Bidirectional coupling refers to the fact that, in cardiac cells, Vm depolarization and the generation of action potentials cause the elevation of [Ca2+]i that is required for contraction (a process referred to as excitation–contraction coupling); conversely, changes of [Ca2+]i control Vm because important membrane currents are Ca2+ dependent. Evidence is mounting that alternans is ultimately caused by disturbances of cellular Ca2+ signalling. Herein we review how two key factors of cardiac cellular Ca2+ cycling, namely the release of Ca2+ from internal stores and the capability of clearing the cytosol from Ca2+ after each beat, determine the conditions under which alternans occurs. The contributions from key Ca2+‐handling proteins (i.e. surface membrane channels, ion pumps and transporters and internal Ca2+ release channels) are discussed.