The pineal neurohormone melatonin functionally synchronizes the photoperiod in the organism. In the last decade, it has become increasingly clear that the pineal gland and melatonin also play an important immunoregulatory role. T helper (Th) cells bear G-protein-coupled melatonin receptors. Activation of melatonin receptors enhances the release of Th cell cytokines, such as gamma-interferon and interleukin-2, as well as novel opioid cytokines which cross-react immunologically with both interleukin-4 and dynorphin B. These mediators may counteract secondary immunodeficiencies, protect mice against lethal viral and bacterial diseases, synergize with interleukin-2 in cancer patients and affect hematopoiesis. Hematopoiesis is apparently influenced by the action of melatonin-induced opioids on kappa-opioid receptors present on stromal bone marrow cells. Most interestingly, gamma-interferon and colony-stimulating factors may modulate the production of melatonin in the pineal gland. A hypothetical pineal-immune-hematopoietic network is, therefore, taking shape. From the immunopharmacological point of view, there is a need for clinical studies on the effect of melatonin in human immunodeficiency-virus-infected patients and cancer patients. In conclusion, melatonin seems to be an important immunomodulatory hormone which deserves to be further studied to identify its relevance in immune-based diseases, its therapeutic indications and its adverse effects.