Since the previous review on the role of opioids in the immune system, numerous investigative teams have contributed to the growing pool of information illustrating the tangible relationship between opioids and immune function, particularly as this association pertains to bacterial and viral pathogens. In addition, the recent cloning of both neural- and immune-derived opioid receptors will ultimately facilitate the identification of molecular events that are responsible for the immunomodulatory effects that are mediated by receptor ligation. Specifically, the administration of opioids in vivo can potentially affect the immune system either through direct interaction with receptors on the effector cells or indirectly, through the ligation of receptors found within the central nervous system. This indirect routing is hypothesized to involve secondary pathways including the hypothalamic pituitary adrenal (HPA) axis and the sympathetic nervous system ultimately resulting in immunomodulation. Consequently, a portion of this review addresses the recent data on leukocyte-derived opioid receptors and the potential immunoregulatory role relative to opiold receptors found within the central nervous system. In addition, recent observations on the effects of opioids and immunocompetence is reviewed from both a molecular and cellular perspective. Finally, the consequence of opioid exposure on the competence of the host immune system to microbial pathogens is summarized.