Calcium (Ca²⁺) is the central second messenger in the translation of electrical signals into mechanical activity of the heart. This highly coordinated process, termed excitation-contraction coupling or ECC, is based on Ca²⁺-induced Ca²⁺ release from the sarcoplasmic reticulum (SR). In recent years it has become increasingly clear that several Ca²⁺ -dependent proteins contribute to the fine tuning of ECC. One of these is the Ca²⁺ /calmodulin-dependent protein kinase (CaMK) of which CaMKII is the predominant cardiac isoform. During ECC CaMKII phosphorylates several Ca²⁺ handling proteins including SR Ca²⁺ release channels or ryanodine receptors (RyR), phospholamban (PLB), and L-type Ca²⁺ channels with multiple functional consequences. CaMKII may also be co-localized to distinct target proteins. In addition, novel data suggest that non- Ca²⁺ transporters such as sarcolemmal Na+ and K+ channels may be regulated by CaMKII and thus be sensitive to Ca²⁺ handling properties and also influence them via electrophysiological effects. CaMKII expression as well as activity are reported to be increased in heart failure and CaMKII overexpression can exert distinct and novel effects on ECC in the heart. In animal models it was found that CaMKII overexpression can induce myocyte hypertrophy and heart failure with altered intracellular Ca²⁺ handling and protein expression leading to reduced SR Ca²⁺ content, typical for heart failure.