Monoamine neuroleptics alter rodents responses to immunization, suggesting that norepinephrine (NE) and serotonin (5HT) are neuroimmunomodulatory in these animals. Although endocrine factors participate in their mechanism(s) of action, recent studies suggest that NE and 5HT also interact more directly with immunocompetent cells. This review provides an overview of evidence for a direct regulatory link between the nervous and immune systems and further speculates on the process by which NE and 5HT realize in part, their neuroimmunomodulatory potential. Anatomical data show that noradrenergic fibers of the sympathetic nervous system innervate lymphoid organs providing a channel of communication between neurons and lymphocytes. Presumably neural signals transmitted by NE are received by platelets that in turn, transduce them via 5HT into immunomodulatory messages. It is proposed that NE alters the capacity of platelets to sequester and/or catabolize 5HT, thus regulating its physiologically active pool in the plasma. Macrophages possess a 5HT uptake system, the kinetic properties of which make them sensitive to changes in plasma levels of the amine. Thus, through its ability to regulate plasma levels of 5HT, an immunosuppressive amine with access to macrophages, the nervous system can influence cells involved in antigen recognition. Support for this hypothetical immunomodulatory mechanism is gleaned from clinical and experimental studies. For example, individuals suffering emotional trauma are more susceptible than others to developing physical illness. It is of interest that platelet 5HT pharmacodynamics are often abnormal in patients with psychological disorders characterized by catecholamine deficits. Similar platelet changes have been achieved experimentally by treating rats with catecholamine antimetabolites. Additional support for the hypothesis derives from aging research since 'monoamine imbalance' and immune dysfunction are co-characteristics of senescence. In aging rodents and humans, central catecholamine deficits are associated with a decreased platelet affinity for 5HT and an increased plasma content of 5HT. Thus, emotional, spontaneous (age-related), or experimental changes in monoamine homeostasis have the potential to increase the risk of disease in affected individuals. Perhaps part of this effect results from endocrine perturbations associated with the trauma. However, a direct interaction between the nervous and immune systems involving monoamines is also possible, and a need for future study of this potentially significant mechanism for neuroimmunomodulation is indicated.