The multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulates a rich variety of downstream targets in heart. Ca(2+) homeostatic proteins are important CaMKII targets that support myocardial excitation-contraction coupling. Under stress conditions, excessive CaMKII activity promotes heart failure and arrhythmias, in part through actions at Ca(2+) homeostatic proteins. Here, we briefly review the molecular and cellular physiology of CaMKII in myocardium.