Our knowledge and understanding of the normal and diseased heart has advanced significantly over the past decade. Evidence indicates that several signaling pathways involved in the induction of cardiac disease and heart failure are associated with abnormal calcium handling by the sarcoplasmic reticulum proteins: calcium-ATPase pump and phospholamban. Indeed, the failing heart is characterized by impaired removal of cytosolic calcium, reduced loading of the cardiac sarcoplasmic reticulum, and defective calcium release, culminating in impairment of cardiac diastolic and systolic function. This review summarizes studies which highlight the key role of the sarcoplasmic reticulum proteins, calcium-ATPase pump and phospholamban, in the regulation of cardiac function; the significance of the phospholamban interaction with the calcium-ATPase pump through transgenic animal models; the recent findings of the inhbitor-1 of protein phosphatase-1 as a new potential therapeutic agent in heart failure; and finally, the discoveries of human phospholamban mutations leading to disease states.