Even though cytokines may fundamentally act as local factors, the recent advances in the knowledge of neuroimmunomodulation (NIM) would suggest the existence of a central regulation of their secretion and activity. Several neuroactive substances have appeared to influence cytokine secretion, and on the other hand cytokines may modulate the neuroendocrine functions. However, at present only for the pineal gland, whose fundamental NIM role is well known, it is possible to recognize reciprocal influences between cytokine action and pineal endocrine activity, suggesting the existence of feedback mechanisms responsible for a central regulation of cytokine network. Melatonin (MLT), which is the most investigated pineal immunomodulating hormone, may stimulate IL-2 release by T helper-1 (TH-1) lymphocytes and that of IL-12 by dendritic cells (DC), whereas both IL-2 and IL-12 would inhibit MLT release. The physiological significance of IL-2IL-12MLT interactions would be the maintenance of an effective TH-1-dependent cellular immunity, including the anticancer immune response. A third possible pineal-cytokine feedback mechanism involves tumor necrosis factor-alpha (TNF-alpha) secretion, with a stimulatory effect of TNF-alpha on MLT release and an inhibitory one of MLT on TNF-alpha production. This finding would explain the anti-cachectic property of MLT itself. A further knowledge of pineal-cytokine interactions, as well as of other endocrine-immune circuits, will allow a better definition of the physiopathology of human chronic immunoinflammatory diseases, whose clinical course has appeared to be influenced by psychoemotional factors.