Gene therapy to treat heart failure has evolved into a growing field of investigation yielding remarkable results in preclinical models. Whether these results will persist in clinical trials remains to be seen. However, researchers still face a number of obstacles that need to be overcome before this treatment can be employed effectively. Efforts are required to identify better vectors with minimal side effects and maximal efficiency and durability. There is also a need to develop less invasive and more effective techniques to deliver these vectors. This review will discuss different methods to achieve these goals, the various pathologic mechanisms that have been targeted so far and those with strong potential for use in the future.