The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is the CaMK isoform predominantly found in the heart. Cardiac myocytes signaling during excitation-contraction coupling (ECC) is described by the increase in intracellular Ca2+ concentration. In consequence, CaMKII is activated thereby phosphorylating several important Ca2+ handling proteins with multiple functional consequences for cardiac myocytes. Specific CaMKII overexpression in the heart and in isolated myocytes of animals can exert distinct and novel effects on ECC. CaMKII activity and expression are reported to be increased in cardiac hypertrophy, in human heart failure, as well as in animal models thereby contributing to cardiac disease through a regulation process termed excitation-transcription coupling (ETC). In the present review important aspects of the role of CaMKII in ECC and ETC are summarized with an emphasis on recent novel findings.