Opioid receptors and opioid agonists are widespread throughout nature. Endogenous opioids mediate complex functions in animals and in humans. The opioid system in humans plays a central role in pain control and is a key mediator of hedonic homeostasis, mood, and well-being. This system also regulates responses to stress and several peripheral physiologic functions, including respiratory, gastrointestinal, endocrine, and immune systems. This article provides an overview of the basic physiology of opioids, reviews opioid pharmacology, and attempts to address several issues of current importance in the management of patients with established long-term opioid therapy.