Abstract: Recent advances in our understanding of the pathophysiology of myocardial dysfunction in the setting of congestive heart failure have created a new opportunity in developing nonpharmacological approaches to treatment. Gene therapy has emerged as a powerful tool in targeting the molecular mechanisms of disease by preventing the ventricular remodeling and improving bioenergetics in heart failure. Refinements in vector technology, including the creation of recombinant adeno-associated viruses, have allowed for safe and efficient gene transfer. These advancements have been coupled with evolving delivery methods that include vascular, pericardial, and direct myocardial approaches. One of the most promising targets, SERCA2a, is currently being used in clinical trials. The recent success of the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease phase 2 trials using adeno-associated virus 1-SERCA2a in improving outcomes highlights the importance of gene therapy as a future tool in treating congestive heart failure.