Persistent dysfunctions emerging from use and discontinuation of 5-alpha reductase inhibitors (PD-5ARI) may be explained as the aftermath of a pathological recovery from microvasculopathy or ischemia in multiple systems. Focusing on persistent sexual dysfunction, the most common class of symptoms: 5ARIs’ inhibition of angiogenesis leads to stress on penile microvasculature, depriving the tissue of blood supply and oxygen. These hypoxic conditions lead to tissue injury and atrophy, triggering a pathological recovery that further alters penile tissue, including smooth muscle loss, fibrosis, damage to vascular architecture and impairment of neural pathways supporting arousal and erectile function. This damaging cascade may result in severe and lasting sexual dysfunction. Persistent neuropsychiatric, cognitive, sensory and sleep dysfunctions emerging from 5ARI treatment may similarly be explained as pathological responses to microvasculopathy or ischemia in supporting structures, particularly those in the limbic system. Systemic spread is proposed to arise from a vicious cycle of tissue injury, oxidative stress and proinflammatory activity which spreads via the vascular network, leading to systemic endothelial dysfunction. The latter may in turn set off a damaging cascade in other organs and tissues. Risks of developing PD-5ARI may arise from 5ARI-mediated disruptions of vascular tone, angiogenesis and neoangiogenesis. Pharmacovigilance data, animal studies and human studies provide converging evidence for the proposed etiopathology. It is, moreover, consistent with variable presentation and severity of PD-5ARI symptoms; irreversibility of symptoms; typically normal results of clinical lab tests; and resistance to treatment.