Heart failure is a major cause of morbidity and mortality in Western countries. While progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, for example, was initially envisioned as a treatment strategy for inherited monogenic disorders. It is now apparent that gene therapy has broader potential, which also includes acquired polygenic diseases such as heart failure. Advances in the understanding of the molecular basis of conditions such as these, together with the evolution of increasingly efficient gene transfer technology, has placed congestive heart failure within the reach of gene-based therapy.