During the past decade, several progresses have been made for a deeper understanding of the regulatory factors that mediate normal erectile function, although the mechanisms involved in pathophysiology of erectile dysfunction (ED) remain to be completely elucidated. However, dramatic advances in the management of ED have occurred. Many drugs are now available, with oral pharmacotherapy representing the first-line option for most patients. ED is a common condition associated with aging but not necessarily a consequence of aging. The most important risk factors are associated to the impaired balance between contractant and relaxant mechanisms of penile structures, resulting in arterial insufficiency and defect smooth muscle relaxation. The normal erectile function involves the synthesis of NO, the main neurotransmitter mediating erectile processes, and the subsequent accumulation of cyclic GMP (cGMP). The NO formation, and therefore the erection, is strictly controlled by the activity of NO synthase (NOS) isoenzymes, whereas cGMP degradation is specifically controlled by phosphodiesterase type 5 (PDE5), which promotes smooth muscle tone and terminates erection. The regulation of the activity of these 2 counteracting enzymes allows the penis to be contracted for the majority of the time. Androgens play a pivotal role in these mechanisms by regulating both NOS and PDE5 activity. This peripheral and antithetic role of androgens seems to regulate penile erections synchronizing erectile processes to sexual desire. Moreover, the androgen-dependent activity of PDE5 mirrors the unresponsiveness of certain patients with ED to PDE5 inhibitors (PDE5i), the most widely prescribed oral drugs. In fact, PDE5i cannot work if the target enzyme is lacking. This suggests the importance to test testosterone plasma levels in those patients with ED who do not respond to PDE5i. In conclusion, a better understanding of the pathogenic factors of ED will be useful to appropriately design pharmacotherapy and improve clinical management depending on the unique condition of each patient.