It is generally accepted that androgens are critical for development, growth, and maintenance of penile erectile tissue. However, their role in erectile function, especially in humans, remains controversial. Clinical and preclinical studies have suggested that venoocclusion is modulated by the tone of the vascular smooth muscle of the resistance arteries and the cavernosal tissue and a balance between trabecular smooth muscle content and connective tissue matrix. In men with erectile dysfunction, venous leakage is thought to be a common condition among nonresponders to medical management and is attributed to penile smooth muscle atrophy. In the animal model, androgen deprivation produces penile tissue atrophy concomitant with alterations in dorsal nerve structure, endothelial morphology, reduction in trabecular smooth muscle content, and increased deposition of extracellular matrix. Further, androgen deprivation results in accumulation of fat-containing cells (adipocytes) in the subtunical region of the corpus cavernosum. Androgen deficiency diminishes protein expression and enzymatic activity of nitric oxide synthases (eNOS and nNOS) and phosphodiesterase type 5 (PDE5). The androgen-dependent loss of erectile response is restored by androgen administration but not by administration of PDE5 inhibitors alone. These data suggest that androgens regulate trabecular smooth muscle growth and connective tissue protein synthesis in the corpus cavernosum. Further, androgens may stimulate differentiation of progenitor cells into smooth muscle cells and inhibit their differentiation into adipocytes. Thus, we conclude that androgens exert a direct effect on penile tissue to maintain erectile function and that androgen-deficiency produces a metabolic and structural imbalance in the corpus cavernosum, resulting in venous leakage and erectile dysfunction. .