Heart failure associated with coronary artery disease is a major cause of morbidity and mortality. Recent developments in the understanding of the molecular mechanisms of heart failure have led to the identification of novel therapeutic targets which, combined with the availability of efficient gene delivery vectors, offer the opportunity for the design of gene therapies for protection of the myocardium. Viral-based therapies have been developed to treat polygenic and complex diseases such as myocardial ischaemia, hypertension, atherosclerosis and restenosis. Some of these experimental therapies are now undergoing clinical evaluation in patients with cardiovascular diseases. In this review we will focus on the latest advances in the field of gene therapy for treatment of heart failure and their clinical application.