The present review focusses on the regulation and interplay of cardiac SR Ca²⁺ handling proteins involved in SR Ca²⁺ uptake and release, i.e., SERCa2/PLN and RyR2. Both RyR2 and SERCA2a/PLN are highly regulated by post-translational modifications and/or different partners’ proteins. These control mechanisms guarantee a precise equilibrium between SR Ca²⁺ reuptake and release. The review then discusses how disruption of this balance alters SR Ca²⁺ handling and may constitute a first step toward cardiac damage and malignant arrhythmias. In the last part of the review, this concept is exemplified in different cardiac diseases, like prediabetic and diabetic cardiomyopathy, digitalis intoxication and ischemia-reperfusion injury.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculares