Calcium (Ca(2+)) 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 Ca(2+)-induced Ca(2+) release from the sarcoplasmic reticulum (SR). In recent years it has become increasingly clear that several Ca(2+)-dependent proteins contribute to the fine tuning of ECC. One of these is the Ca(2+)/calmodulin-dependent protein kinase (CaMK) of which CaMKII is the predominant cardiac isoform. During ECC CaMKII phosphorylates several Ca(2+) handling proteins with multiple functional consequences. CaMKII may also be co-localized to distinct target proteins. 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 and in isolated myocytes of animals. In the present review we summarize important aspects of the role of CaMKII in ECC with an emphasis on recent novel findings.