The idea that opioids modulate the immune system is not new. By the late 19th century, Cantacuzene, used morphine to suppress cellular immunity and lower the resistance of guinea pigs to bacterial infection. While exogenous opioids mediate immunosuppression, endogenous opiates exert opposite actions. Acute and chronic opioid administration is known to have inhibitory effects on humoral and cellular immune responses including antibody production, natural killer cell activity, cytokine expression, and phagocytic activity. Opiates behave like cytokines, modulating the immune response by interaction with their receptors in the central nervous system and in the periphery. Potential mechanisms by which central opiates modulate peripheral immune functions may involve both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. The presence of opioid receptors outside the central nervous system is increasingly recognized. Those receptors have been identified not only in peripheral nerves but also in immune inflammatory cells. The immunosuppression mediated by opiates may explain the increased incidence of infection in heroin addicts. Opiates may also promote immunodeficiency virus infection by decreasing the secretion of alpha and beta chemokines (important inhibitory cytokines for the expression of HIV) and at the same time increasing the expression of chemoreceptors CCR5 and CCR3, coreceptors for the virus. The fact that peripheral immunosupression is mediated at least in part by opioid receptors located in the central nervous system and that intrathecally administered opioids do not exert the same immunosuppressive effects may have important clinical implications for those patients receiving long-term opioid therapy for malignant and nonmalignant pain.