Pineal gland melatonin is the darkness hormone, while extra-pineal melatonin produced by the gonads, gut, retina, and immune competent cells acts as a paracrine or autocrine mediator. The well-known immunomodulatory effect of melatonin is observed either as an endocrine, a paracrine or an autocrine response. In mammals, nuclear translocation of nuclear factor.-light-chain-enhancer of activated B cells (NF-kappa B) blocks noradrenaline-induced melatonin synthesis in pinealocytes, which induces melatonin synthesis in macrophages. In addition, melatonin reduces NF-kappa B activation in pinealocytes and immune competent cells. Therefore, pathogen-or danger-associated molecular patterns transiently switch the synthesis of melatonin from pinealocytes to immune competent cells, and as the response progresses melatonin inhibition of NF-kappa B activity leads these cells to a more quiescent state. The opposite effect of NF-kappa B in pinealocytes and immune competent cells is due to different NF-kappa B dimers recruited in each phase of the defense response. This coordinated shift of the source of melatonin driven by NF-kappa B is called the immune-pineal axis. Finally, we discuss how this concept might be relevant to a better understanding of pathological conditions with impaired melatonin rhythms and hope it opens new horizons for the research of side effects of melatonin-based therapies.