Cardiovascular diseases remain a major cause of morbidity and mortality. Despite significant gains in medical and surgical treatment of these conditions, the burden imposed continues to increase, particularly as the population ages. Hence, there exists an impetus to explore novel therapeutic approaches. Gene therapy, broadly defined as the use of nucleic acid sequences as medicine, is an example of such a novel approach. The potential of gene therapy has been explored in several models of both inherited monogenic and acquired polygenic cardiovascular diseases, such as heart failure and arrhythmia. Exciting developments in gene transfer technology and important insights into the molecular basis of these common diseases have placed them within reach of gene-based therapy.