Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease associated with cardiac arrest in the paediatric population. The disease was first described as a novel clinical entity by 1995. With the advancements of genetics the discovery of the molecular substrate of the showed that CPVT results from inherited abnormalities of intracellular Ca2+ regulation caused by dominant mutations in the RYR2 gene, encoding the cardiac Ca2+ release channel (ryanodine receptor isoform 2 [RyR2]) and by recessive mutations in the CASQ2 gene, encoding cardiac calsequestrin isoform The discovery of the molecular substrate of CPVT has fuelled basic science studies to characterize RYR2 and CASQ2 mutations in vitro and in vivo, leading to important advancements in the understanding of intracellular Ca2+ regulation and its relevance to arrhythmogenesis. In this presentation I will provide an overview of the developments that have occurred in the characterization of functional consequences of RYR2 mutations and their link to understanding arhythmogenesis in CPVT patients. The presentation will provide a concise overview of the physiology of Ca2+ handling in the sarcoplasmic reticulum (SR) and its relevance to rhythm maintenance. Than I will provide a discussion on how mutations in RyR2 disrupt the Ca2+ handling system, leading to cardiac arrhythmias. Finally, I will address how the understanding of the pathophysiology of the disease may lead to novel therapeutic strategies.