In this paper we discuss recent experimental and clinical findings which lead us to propose that prolonged rhythmic exercise can activate central opioid systems by triggering increased discharge from mechanosensitive afferent nerve fibers (Group III or A-delta) arising from contracting skeletal muscle. We review evidence that supports the concept that many of the cardiovascular, analgesic, and behavioral effects of exercise are mediated by this mechanism and that the same or similar mechanisms are responsible for the central and peripheral effects of acupuncture. Based on this hypothesis, and supporting evidence from human and animal studies, we suggest a mechanism and a potential therapeutic role for exercise in the treatment of selected patients with disorders as diverse as hypertension, addiction, depression, and anorexia nervosa.