This presentation will cover the history, recent developments in, and implications of the ability of both the immune and neuroendocrine systems to produce POMC. The discovery of POMC in immune cells was one of the events that heralded a molecular understanding of neuroimmunomodulation. This, together with the presence of opiate and ACTH receptors on lymphocytes and macrophages, provided the first biochemical circuit for which the same signal molecules and receptors could be used for intrasystem regulation, as well as bidirectional communication between the immune and neuroendocrine systems. Today we have a quite good understanding of the regulation and processing of POMC in immune cells, as well as the interaction of its product peptides with other cytokines. For instance, IL-1 causes POMC production by immune cells, and the POMC product, α-MSH, in turn, acts functionally as an IL-1 antagonist. In the past year, the expression of full-length POMC mRNA has been reported and this solved one of the paradoxes with respect to POMC production, processing, and secretion. We provide data on these developments together with quite startling findings on the physiologic function of POMC peptides in the immune system. Among these are the local antinociceptive effects of immune cell-derived β-endorphin, altered hematopoiesis in opiate receptor-deficient animals, and the diagnosis of ACTH insensitivity by a deficiency of ACTH receptors on lymphocytes.