The cardiac isoform of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) is a calcium ion (Ca²⁺) pump powered by ATP hydrolysis. SERCA2a transfers Ca²⁺ from the cytosol of the cardiomyocyte to the lumen of the sarcoplasmic reticulum during muscle relaxation. As such, this transporter has a key role in cardiomyocyte Ca²⁺ regulation. In both experimental models and human heart failure, SERCA2a expression is significantly decreased, which leads to abnormal Ca²⁺ handling and a deficient contractile state. Following a long line of investigations in isolated cardiac myocytes and small and large animal models, a clinical trial is underway that is restoring SERCA2a expression in patients with heart failure by use of adeno-associated virus type 1. Beyond its role in contractile abnormalities in heart failure, SERCA2a overexpression has beneficial effects in a host of other cardiovascular diseases. Here we describe the mechanism of Ca²⁺ regulation by SERCA2a, examine the beneficial effects as well as the failures, risks and complexities associated with SERCA2a overexpression, and discuss the potential of SERCA2a as a target for the treatment of cardiovascular disease.