Heart failure (HF) is associated with systolic and diastolic dysfunction caused by abnormalities in intracellular Ca2+-handling and structural remodeling. Several targets accompanied with the remodeling processes have been identified: The sarcoplasmic reticulum (SR) Ca2+-ATPase protein levels were found to be downregulated and paralleled by a reduced SR Ca2+-uptake in the failing heart. In contrast, the sarcolemmal Na+/Ca2+-exchanger (NCX) was found to be increased (protein level as well as activity) thereby even more effectively competing for Ca2+ removal from the cytosol with the reduced SR Ca2+-ATPase activity. This reciprocal expression of the two most important intracellular Ca2+-transport proteins occurs during the pathogenesis of heart failure. The net effect is an impaired SR Ca2+-loading which leads to smaller intracellular Ca2+ transients and elevated diastolic Ca2+ levels. The result of impaired contractility such as reduced contractile force and diastolic dysfunction are well accepted determinants in the failing heart. Ca2+-homeoastasis of cardiac myocytes is regulated by phosphorylation of several key proteins thereby controlling Ca2+-fluxes but may also cause ionic disruption in heart failure. A major regulatory kinase of Ca2+-handling in cardiac myocytes is the Ca2+/calmodulin-dependent protein kinase II (CaMKII). It is a protein kinase that modulates several important Ca2+-dependent regulatory proteins in myocytes, such as the SR Ca2+-release channel (ryanodine receptor, RyR2), phospholamban (PLB), L-type Ca2+-channels and also Na+-channels. The predominant cardiac isoform is CaMKIIδ. CaMKII may be involved in the pathogenesis of hypertrophy and heart failure since CaMKIIδ transgenic mice develop severe heart failure and CaMKIIδ knockout prevents cardiac hypertrophy. There is a direct association of CaMKIIδ and the RyR2 which has been shown to increase diastolic SR Ca2+-leak leading also to arrhythmogenesis in CaMKIIδ transgenic mice. SR Ca2+-leak can be markedly reduced by CaMKII inhibition leading to increased SR ca content and positive inotropic effects and reduced arrhythmogenesis providing evidence for a direct relationship between CaMKII activity and reduced SR Ca2+-load due to increased Ca2+-spark frequency.