Heart disease remains the leading cause of death and disability in the Western 
world. Current therapies aim at treating the symptoms rather than the 
subcellular mechanisms, underlying the etiology and pathological remodeling in 
heart failure. A universal characteristic, contributing to the decreased 
contractile performance in human and experimental failing hearts, is impaired 
calcium sequestration into the sarcoplasmic reticulum (SR). SR calcium uptake is 
mediated by a Ca(2+)-ATPase (SERCA2), whose activity is reversibly regulated by 
phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA and 
phosphorylation of PLN relieves this inhibition. However, the initial simple 
view of a PLN/SERCA regulatory complex has been modified by our recent 
identification of SUMO, S100 and the histidine-rich Ca-binding protein as 
regulators of SERCA activity. In addition, PLN activity is regulated by 2 
phosphoproteins, the inhibitor-1 of protein phosphatase 1 and the small heat 
shock protein 20, which affect the overall SERCA-mediated Ca-transport. This 
review will highlight the regulatory mechanisms of cardiac contractility by the 
multimeric SERCA/PLN-ensemble and the potential for new therapeutic avenues 
targeting this complex by using small molecules and gene transfer methods.