Erectile dysfunction (ED) is a major public health problem that seriously affects the quality of life of patients and their partners. ED is mainly associated with vascular disease, diabetes, smoking, and radical prostatectomy, and its prevalence increases significantly with aging. Vasculogenic ED, specifically corporal veno-occlusive dysfunction (CVOD), is caused by the impairment of the relaxation of the smooth muscle in the penile corpora cavernosa and occurs in 2/3 of cases, whereas the less common neurogenic ED is due to a defective nitrergic neurotransmission triggered by the sexual stimulus, either at the central hypothalamic and spinal levels or at the penile nerves. Based on animal and cell studies, neurogenic ED is assumed to be caused mainly by: (a) an insufficient synthesis of nitric oxide (NO) due to a decrease in the levels of the penile neuronal nitric oxide synthase (PnNOS) or the impairment of its regulation by protein effectors (NMDA receptor, protein inhibitor of nNOS: PIN), occurring in the neuronal bodies or nerve terminals, or (b) a loss of the cells themselves by apoptosis caused by the induction of inducible NOS (iNOS) and the production of peroxynitrite. In contrast vasculogenic ED, although may involve endothelial damage and down-regulation of endothelial NOS (eNOS), appears to be mainly caused by the relative loss of smooth muscle cells and replacement by collagen fibers (fibrosis) that impairs tissue compliance. In this case, iNOS induction may not be deleterious, but a defense mechanism preventing excessive collagen deposition. Gene therapy to the penile corpora cavernosa of cDNAs expressing PnNOS or eNOS, or counteracting PIN, has been effective in ameliorating ED in the aging rat model that exhibits both neurogenic ED and CVOD. cDNA constructs for other genes involved in the control of penile erection have also been successfully tested. Gene transfer into the penis may soon translate to the clinic as a therapy aimed to cure the underlying conditions in ED, including fibrosis, as opposed to the facilitation of erection on demand offered by the current oral therapies.