Erectile dysfunction is a disease that affects half of American men aged over 50 years. Many men respond to oral phosphodiesterase inhibitors but many do not. For this reason, many researchers are focusing their efforts on developing novel gene therapies for the treatment of erectile dysfunction. Aided by the meticulous characterization of the molecular cascades involved in the physiology of erection, several groups around the world are studying gene therapies in animal models, and one in a human clinical trial. Here we provide a review of the pathophysiology of erectile dysfunction and how it relates to the molecular targets of novel gene therapeutics. The field of gene therapy for the treatment of erectile dysfunction is continually growing, and this decade will likely see exciting results as the expansion from animal models to human clinical trials continues.