In the past several years we demonstrated that the pineal neurohormone melatonin has immunoenhancing properties and can counteract the immunodepression that may follow acute stress, drug treatment, and viral diseases or aging. Several laboratories have subsequently confirmed and extended our findings. It soon appeared evident that T-derived cytokines constitute the main mediators of the immunological effect of melatonin. We have recently found a high affinity (Kd: 346 +/- 24 pM) binding site for 125I-melatonin on T-helper-type 2 lymphocytes in the bone marrow. Activation of this putative melatonin receptor, with both physiological and pharmacological concentrations of melatonin, resulted in an enhanced production of interleukin-4 (IL4), which in turn acted on bone marrow stromal cells and induced the release of hematopoietic growth factors. This melatonin-cytokine cascade showed the remarkable capacity of rescuing hematopoietic functions in mice treated with cancer chemotherapeutic compounds without interfering with the anticancer action of these agents. The very low concentration (0.1 nM) at which melatonin is active may well reflect a physiological function of endogenous melatonin. The pineal gland has been, in fact, reported to signal the blood forming system. The evidence of IL4 involvement is relevant to our understanding of many melatonin effects and may be part of a pineal-immune axis involving also Th1 cytokines. The ability of rescuing hematopoiesis against the toxic action of cancer chemotherapeutic compounds and the presence of high-affinity IL4 receptors on human tumors provide a further promising rationale for the clinical use of melatonin.