Congestive heart failure is an inexorable disease associated with unacceptably high morbidity and mortality. Preclinical results indicate that gene transfer using various proteins is a safe and effective approach for increasing function of the failing heart. In the current review, we provide a summary of cardiac gene transfer in general and summarize findings using adenylyl cyclase 6 as therapeutic gene in the failing heart. We also discuss the potential usefulness of a new treatment for congestive heart failure, paracrine-based gene transfer.