OPIUM IS AN EXTRACT derived from the poppy plant, Papaver somniferum, which, for many centuries, has been used to produce analgesia and alleviate pain. Opium contains several important alkaloid constituents, which vary markedly in their pharmacologic actions. Some of these alkaloids, such as morphine and codeine, are useful therapeutically. In 1806, Serturner isolated morphine from opium; this was a major advancement in opioid research.1 The term opioid was coined by Acheson2 to denote compounds with morphine-like properties despite their chemically diverse structures. However, it was not until 167 years later that the pharmacology of opioids was defined at the receptor level.3 Although morphine is the most widely used analgesic clinically, it produces several undesirable side effects, including nausea, constipation, respiratory depression, and addiction. Chemists have successfully synthesized other forms of opioid molecules in a continuing effort to make analogs with greater selectivity and fewer side effects. The first reports of morphine’s clinical use were provided by a second-century Greek physician, Galen, who administered opium for the relief of pain and to reduce anxiety in those suffering from asthma and congestive heart failure. About A.D. 1000, an Arabic physician, Avicenna, prescribed opium for diarrhea and diseases of the eye.4 In addition to producing analgesia, numerous studies suggest that endogenous opioids are mediators/modulators of: the stress response; immune/inflammatory events; cardiovascular, gastrointestinal, endocrine, and respiratory control; neuronal events related to behavior, learning, memory, perception, and emotion; and regulation of cellular proliferation and survival. Thus, in addition to being effective analgesics, opioids can produce a myriad of pharmacologic actions that might have application in a variety of diseases of the eye. To date, numerous studies have suggested modulatory roles for the opioidergic receptors in neuronal, cardiac, gastrointestinal, endocrine, and immune systems. For example, the ability of opioids to elicit protection against ischemia and other insults has been demonstrated unequivocally in the heart, brain, kidney, and liver of laboratory animals.5,6 Moreover, some investigators have proposed that endogenous opioids should be considered messenger molecules (cytokines) at the crossroads of the inflammatory/immune responses.7 These diverse types of pharmacologic actions of endogenous and exogenous opioid ligands have not been investigated sufficiently in the eye. This review provides an overview of the complexity of opioid receptor-mediated pharmacologic actions in the eye and compares it to reports of similar effects in nonocular systems. Based on existing literature and current data, evidence suggests that opioidergic ligands have the potential to protect against retinopathies, particularly those associated with glaucoma. In this regard, it