The interaction between the brain and the immune system is essential for the adaptive response of an organism against environmental challenges. In this context, the pineal neurohormone melatonin (MEL) plays an important role. T-helper cells express G-protein coupled cell membrane MEL receptors and, perhaps, MEL nuclear receptors. Activation of MEL receptors enhances the release of T-helper cell Type 1 (Th1) cytokines, such as gamma-interferon (gamma-IFN) and IL-2, as well as of novel opioid cytokines. MEL has been reported also to enhance the production of IL-1, IL-6 and IL-12 in human monocytes. These mediators may counteract stress-induced immunodepression and other secondary immunodeficiencies and protect mice against lethal viral encephalitis, bacterial diseases and septic shock. Therefore, MEL has interesting immunotherapeutic potential in both viral and bacterial infections. MEL may also influence haemopoiesis either by stimulating haemopoietic cytokines, including opioids, or by directly affecting specific progenitor cells such as pre-B cells, monocytes and NK cells. MEL may thus be used to stimulate the immune response during viral and bacterial infections as well as to strengthen the immune reactivity as a prophylactic procedure. In both mice and cancer patients, the haemopoietic effect of MEL may diminish the toxicity associated with common chemotherapeutic protocols. Through its pro-inflammatory action, MEL may play an adverse role in autoimmune diseases. Rheumatoid arthritis patients have increased nocturnal plasma levels of MEL and their synovial macrophages respond to MEL with an increased production of IL-12 and nitric oxide (NO). In these patients, inhibition of MEL synthesis or use of MEL antagonists might have a therapeutic effect. In other diseases such as multiple sclerosis the role of MEL is controversial. However, the correct therapeutic use of MEL or MEL antagonists should be based on a complete understanding of their mechanism of action. It is not yet clear whether MEL acts only on Th1 cells or also on T-helper Type 2 cells (Th2). This is an important point as the Th1/Th2 balance is of crucial importance in the immune system homeostasis. Furthermore, MEL being the endocrine messenger of darkness, its endogenous synthesis depends on the photoperiod and shows seasonal variations. Similarly, the pharmacological effects of MEL might also be season-dependent. No information is available concerning this point. Therefore, studies are needed to investigate whether the immunotherapeutic effect of MEL changes with the alternating seasons.