The field of opioid immunomodulation research has experienced tremendous growth in the last five years. Studies have indicated that endogenous and exogenous opioids directly modify cells of the immune system through membrane-associated opioid receptors, as well as indirectly altering immunophysiology through neuroendocrine pathways. These findings suggest an important role for these compounds not only in immune homeostasis but also in the host’s response to infectious pathogens and neoplasia. Surprisingly, the clinical correlation between opioid use and infectious disease has not been fully addressed in spite of its significance to human populations either abusing opioids or utilizing it for pain management. The effort characterizing opioids in biological systems affected by viral, fungal, bacterial and parasitic pathogens has been modest. Consequently, additional in vivo studies elucidating the mechanism(s) of chronic and acute opioid treatment relative to microbial pathogens in both animal models and human subjects is warranted in order to facilitate our understanding of the clinical relevance of these compounds, particularly as it relates to the immune system.