Our understanding of the role of phospholamban in cardiac physiology has evolved over the past two decades to the point where this protein is now understood to be a critical repressor of myocardial contractility. Phospholamban, through its inhibitory effects on the affinity of the cardiac sarcoplasmic reticulum Ca2+ pump for Ca2+, represses both the rates of relaxation and contraction in the mammalian heart. These inhibitory effects can be relieved through (1) phospholamban phosphorylation, (2) down-regulation of phospholamban gene expression, and (3) disruption of the phospholamban-Ca(2+)-ATPase interaction. Thus, genetic approaches and pharmacological interventions, designed to relieve the phospholamban inhibitory action on the cardiac sarcoplasmic reticulum Ca2+ pump and myocardial relaxation, may prove valuable in reversing the effects of several diseases in the mammalian heart. Such interventions could be designed to inhibit the phospholamban phosphatase, stabilize the phosphorylated state of phospholamban, interrupt the phospholamban-Ca(2+)-ATPase interaction, decrease phospholamban transcription, or disrupt phospholamban mRNA stability. Development of such therapeutic strategies to target phospholamban will be an important future goal for the clinical improvement of contractility in the failing heart.