Ryanodine Receptors (RyR) are large ion channels necessary for Ca2+ release from intracellular stores in many cell types. Since RyR was discovered nearly 30 years ago, a fruitful research field has devoted to understanding the physiological regulation of the three protein isoforms in health, and the mechanisms underlying their dysfunction in sickness. This minireview discusses the structural characteristics of RyR2, the cardiac isoform, its regulation during cardiac function and the clinical significance of specific mutations. While hundreds of RyR2 mutations are associated with cardiac disease with different levels of confidence, close to 1500 variants appear in the general population without inducing harmful phenotypes. Hence, studying RyR2 mutations variants may shed light on overall protein regulation and the mechanisms that compensate for constitutive changes in RyR2 function.Sociedad Argentina de Fisiología