Late coupled or delayed after-depolarisations (DADs) in ventricular cardiomyocytes are thought to be the cause of arrhythmic action potentials that can lead to sustained re-entrant arrhythmias. The cause of DADs is the spontaneous release of Ca2+ from the sarcoplasmic reticulum (SR) during diastole. Spontaneous Ca2+ release is normally in the form of a Ca2+ wave that starts at a discrete part of the cardiomyocytes and propagates along the length of the cell. Understanding the subcellular mechanisms of these spontaneous events is critical in designing pharmacological approaches to block the pro-arrhyt hmic event. Initially, this talk will describe work designed to quantify the Ca2+ fluxes associated with the Ca2+ wave based both on intracellular and intra-SR Ca2+ measurements. The data shows how the spontaneous release process copes with moderate levels of cellular Ca2+ load, in particular the role of Ca2+/calmodumin-dependant protein kinase (CaM kinase) in the modulation of Ca2+ waves. At very high cellular Ca2+ values, sustained contraction and cell death is temporarily prevented by mitochondrial Ca2+ uptake. The conventional view of the Ca2+ wave is that it originates as a local Ca2+ release from a cluster of ryanodine receptors (RyR) located within the dyadic cleft of the cardiomyocyte. The local release event (Ca2+ spark) initiates release from an adjacent cluster via the process of Ca2+-induced Ca2+-release, and this “fire-diffuse-fire” process is thought to explain Ca2+ wave propagation. In the final section of the talk, the issue of Ca2+ wave propagation is explored in more detail, in particular the evidence for the role that RyRs out with the dyad may have in the propagation of Ca2+ waves. The data supporting the role of extra-dyadic RyRs also suggests strategies to suppress Ca2+ wave occurrence (and the associated arrhythmic event) without significantly affecting the Ca2+ release from the main clusters of RyRs within the dyadic cleft. Inhibition of non-dyadic RyRs may be part of the explanation for the ability of the novel candidate antiarrythmic drug K201 (formerly JTV519) to suppress spontaneous Ca2+ release.