Gene therapy has been applied to cardiovascular disease for over 20 years but it is the application to heart failure that has generated recent interest in clinical trials. There is laboratory and early clinical evidence that delivery of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy is beneficial for heart failure and this therapy could become the first positive inotrope with anti-arrhythmic properties. In this review we will discuss the rationale for SERCA2a gene therapy as a viable strategy in heart failure, review the published data, and discuss the ongoing clinical trials, before concluding with comments on the future challenges and potential for this therapy.