Within the cardiac cell, the movements of calcium ions are tightly regulated by a number of regulatory proteins including pumps, and channels. The sarcoplasmic reticulum (SR) is in large part responsible for orchestrating these movements for the normal functioning of the cardiomyocyte. Alterations of SR regulatory proteins in failing hearts leads to abnormal Ca(2+) homeostasis and consequently to a deficient contractile state. This review focuses on the roles of SR Ca(2+) regulators in disease states and novel strategies for therapeutic targeting of these pathways.