This paper summarizes the data related to the relations between enkephalins and endorphins and the immune system. It is shown that lymphocytes have surface receptors for endorphins and enkephalins. Furthermore, endorphins and enkephalins can influence several immune functions such as antibody synthesis, lymphocyte proliferation, and natural killer cytotoxicity. It is thus possible that the receptors play a functional role. In view of these observations, several hypotheses are proposed. Endorphins and enkephalins are physiological regulators of the immune response (two-hit opioid peptide lymphocyte receptor hypothesis) and they are humoral mediators between the central nervous system and the immune system. They may play a pathogenic role in a variety of diseases with primary or secondary immunological defects. Finally, enkephalins and endorphins can be considered as immunomodulators and modifiers of the biological response and as such may become a tool in the field of immunotherapy.