Melanocortins play a fundamental role in several basic functions of the organism (sexual activity, feeding, inflammation and immune responses, pain sensitivity, response to stressful situations, motivation, attention, learning, and memory). Moreover, a large body of animal data, some of which were also confirmed in humans, unequivocally show that melanocortins also have impressive therapeutic effects in several pathological conditions that are the leading cause of mortality and disability worldwide (hemorrhagic, or anyway hypovolemic, shock; septic shock; respiratory arrest; cardiac arrest; ischemia- and ischemia/reperfusion-induced damage of the brain, heart, intestine, and other organs; traumatic injury of brain, spinal cord, and peripheral nerves; neuropathic pain; toxic neuropathies; gouty arthritis; etc.). Recent data obtained in animal models seem to moreover confirm previous hypotheses and preliminary data concerning the neurotrophic activity of melanocortins in neurodegenerative diseases, in particular Alzheimer's disease. Our aim was (i) to critically reconsider the established extrahormonal effects of melanocortins (on sexual activity, feeding, inflammation, tissue hypoperfusion, and traumatic damage of central and peripheral nervous system) at the light of recent findings, (ii) to review the most recent advancements, particularly on the effects of melanocortins in models of neurodegenerative diseases, (iii) to discuss the reasons that support the introduction into clinical practice of melanocortins as life-saving agents in shock conditions and that suggest to verify in clinical setting the impressive results steadily obtained with melanocortins in different animal models of tissue ischemia and ischemia/reperfusion, and finally, (iv) to mention the advisable developments, particularly in terms of selectivity of action and of effects.