The cardiac isoform of sarco(endo)plasmic reticulum Ca(2)(+) adenosine triphosphatase (SERCA2a) plays an important role in the contraction and relaxation of cardiac muscle. Phospholamban (PLN) and its homologue sarcolipin (SLN) are the endogenous regulators of SERCA2a. Evidence is accumulating that SERCA2a is intimately involved in the pathogenesis of cardiac hypertrophy and failure. Recent studies using genetically engineered animals revealed the implication of PLN for the development of cardiomyopathic phenotypes. This review focuses on advances in the understanding of molecular regulation of SERCA2a by PLN and SLN, and their implications for cardiac hypertrophy and failure in vivo.