Although pharmacologic therapies have provided gains in reducing the mortality of heart failure, the rising incidence of the disease requires new approaches to combat its health burden. Twenty-five years ago, abnormal calcium cycling was identified as a characteristic of failing human myocardium. Sarcoplasmic reticulum calcium ATPase (SERCA2a), the sarcoplasmic reticulum calcium pump, was found to be a key factor in the alteration of calcium cycling. With the advancement of gene vectors, SERCA2a emerged as an attractive clinical target for gene delivery purposes. Using adeno-associated virus constructs, SERCA2a upregulation has been found to improve myocardial function in animal models. The clinical benefits of overexpressing SERCA2a have been demonstrated in the phase I study Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID). This study has demonstrated that a persistent expression of the transgene SERCA2a is associated with a significant improvement in associated biochemical alterations and clinical symptoms of heart failure. In the coming years, additional targets will likely emerge that are amenable to genetic manipulations along with the development of more advanced vector systems with safer delivery approaches.