Heart failure is a major cause of morbidity and mortality in western countries. While progress in current treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore novel therapeutic strategies. Clinicians and researchers alike have thus looked towards novel adjunctive therapeutic strategies, including gene-based therapy for congestive heart failure (CHF). Advances in the understanding of the molecular basis of CHF, combined to the evolution of increasingly efficient gene transfer technology, have placed congestive heart failure within reach of gene-based therapy. This review will discuss issues related to gene vector systems, gene delivery strategies, and gene targets for intervention in the setting of CHF.