This discussion summarizes the potential differences in physiologically and pharmacologically induced erections and highlights the possible differences in the pathways facilitated by oral versus intracavernosal agents in penile erection. Oral agents act in conjunction with sexual stimulation either increasing corporal smooth muscle relaxation or attenuating smooth muscle contraction. However, their efficacy is dependent on sexual stimulation. Intracavernosal administration of phosphodiesterase type 5 inhibitor (sildenafil) or short-acting alpha adrenergic receptor antagonist (phentolamine), in the absence of sexual stimulation, does not initiate penile erection. In contrast, intracavernosal administration of PGE1 or papaverine induces erection independent of sexual stimulation. Thus, oral agents are not direct mediators of smooth muscle relaxation and act to facilitate relaxation in response to sexual stimulation, while intracavernosal agents directly mediate smooth muscle relaxation, independent of sexual stimulation. Although, considerable advances have been made in elucidating the physiology and pharmacology of erectile function, details of the signal transduction pathways affected by these agents in the penile corpus cavernosum are yet to be fully investigated. International Journal of Impotence Research (2000) 12, Suppl 1, S81-S88