This review provides an overview of the immunological effects of commonly used analgesic opioid drugs, focusing mainly on two aspects: the mechanisms involved and the potential clinical relevance. The immunomodulatory effects of morphine have been characterized in animal and human studies. Morphine decreases the effectiveness of both natural and acquired immunity, interfering with intracellular pathways involved in immune regulation, both directly and indirectly via the activation of central receptors. The mechanisms and the targets at the basis of opioid-induced immunomodulation have started to be elucidated, demonstrating an interaction between opioid receptors and several molecules involved in the complex and well orchestrated immune response, such as transcription factors and receptors of both myeloid and lymphoid cells. Due to their widespread and expanding use, the immunological effects of opioid are receiving considerable attention because of concerns that opioid-induced changes in the immune system may affect the outcome of surgery or of variety of disease processes, including bacterial and viral infections and cancer. It is also emerging that not all opioids induce the same immunosuppressive effects and evaluating each opioid profile is important for appropriate analgesic selection. The impact of the opioid-mediated immune effects could be particularly dangerous in selective vulnerable populations, such as the elderly or immunocompromised patients. Indeed, it is evident that the possibility of reaching adequate and equivalent pain control by choosing either immunosuppressive drugs or drugs without an effect on immune responses may be an important consideration in opioid therapy.