Increases in diastolic Ca2+ and impaired relaxation in failing hearts have been suggested to reflect the deteriorated function of the sarcoplasmic reticulum Ca-ATPase (SERCA2), whose activity is regulated by phospholamban (PLN). PLN is a reversible inhibitor of SERCA2's Ca2+ affinity and cardiac contractility. Studies in genetically altered mouse models have demonstrated that the levels and the degree of PLN phosphorylation are critical in modulating basal Ca2+ handling and contractility. Correspondingly, the depressed contractility in experimental and human heart failure is partially attributed to increased inhibition by PLN due to: (a) increases in PLN/SERCA2; and (b) decreases in PLN phosphorylation. The attenuated PLN phosphorylation is associated with increased type 1 phosphatase, which reflects dephosphorylation or inactivation of its inhibitor 1. Indeed PLN ablation was successful in rescuing cardiac remodelling and dysfunction in several heart failure mouse models, and inhibition of the phosphatase activity restored contractile parameters in failing rat hearts. Recently, two human PLN mutations, associated with either absence or sustained dephosphorylation of PLN, were linked to dilated cardiomyopathy. Thus, PLN modulation appears to be of paramount importance in humans, and further investigation into PLN function in higher mammalian species may provide insights into its potential as a therapeutic modality in heart failure.