Vascular disorders are the leading causes of organic erectile dysfunction (ED). Most cases of arteriogenic ED are associated with vascular risk factors such as hypercholesterolemia, atherosclerosis, diabetes mellitus, hypertension, and smoking. These conditions impair vascular structure directly or indirectly by facilitating oxidative damage due to accumulation of reactive oxygen and nitrogen species such as superoxide (O 2 − ), hydrogen peroxide (H 2 O 2 ), hydroxyl radicals and peroxynitrite (O=NOO − ). Clinical studies have shown that the degree of arteriogenic ED cannot be predicted exclusively by the arterial integrity, suggesting that it involves local changes within penile smooth muscle cells, endothelium, nerves, and microvasculature. It is thought that arterial occlusion and subsequent lack of erectile tissue perfusion, nutrient deficiency, hypoxia, and accumulation of waste products constitute an environment hospitable to free radical formation and detrimental to nitric oxide (NO) bioavailability. Studies of animal and cell culture models have revealed that exposure to ischemia and hypoxia triggers a cascade of cellular and molecular changes in the erectile tissue with devastating impact on its structure and function. These alterations involve cytotoxic radicals, nitric oxide synthase (NOS), eicosanoids, neurotoxic elements, and growth factors and lead to impairment of NO/cGMP pathway, smooth muscle dysfunction, microvascular damage, and neurodegeneration. Ultimately, these events lead to erectile tissue fibrosis and the failure of penile veno-occlusive mechanism. These local changes in the hypoxic erectile tissue may explain the failure of revascularization surgery to completely cure arteriogenic ED and imply the need for newer therapeutic strategies to remove cytotoxic and neurotoxic elements from the chronically ischemic penis.