Congestive heart failure is a major cause of morbidity and mortality in the United States. Although progress in conventional treatments is making steady and incremental gains to decrease heart failure mortality, there is a critical need to explore new therapeutic approaches. Gene therapy was initially applied in the clinical setting for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as congestive heart failure. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within the reach of gene-based therapy. Furthermore, the recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum Ca²⁺ ATPase pump along with the start of more recent phase 1 trials are ushering in a new era of gene therapy for the treatment of heart failure.