Nitric oxide has been identified as an Endothelium-Derived Relaxing Factor (EDRF). Non adrenergic-non cholinergic nerves synthesise and release nitric oxide, thus modulating the arterial tone. Nitric oxide synthase exists either as a constitutive enzyme in many cell types and as an inducible form expressed under immunological stimulation. Nitric oxide is also involved in the non adrenergic-non cholinergic neurotransmission that leads to smooth muscle relaxation in the corpus cavernosum. Similarly nitric oxide induces reduction of cytosolic free Ca++ as a result of activation of the soluble form of guanylyl cyclase. VIP and nitric oxide may function as co-transmitters. Relaxation of the corpus cavernosum is blocked by methylene blue which inhibits cyclic GMP synthesis; so, high flow priapism refractory to medical and surgical treatments can be managed successfully by intracavernous methylene blue. Moreover it is suggested that enhanced alpha 1-adrenergic mediated constrictor tone and penile flaccidity in diabetic men may respond to exogenous generators of nitric oxide. We postulate that relaxation of the corpus cavernosum, started by nitric oxide in response to non adrenergic-non cholinergic neurotransmission, could be amplified and maintained by nitric oxide production as a result of platelet trapping in the corpus cavernosum during the first phase of the penile erection.