Pituitary melanotroph and corticotroph cells produce and secrete peptides from the multifunctional precursor protein proopiomelanocortin (POMC). Stimulation of the secretory activity of both cell types involves production of cyclic 3′5′‐adenosine monophosphate (cAMP) and increases in the concentration of intracellular Ca²⁺. The increase in secretory activity is accompanied by enhanced expression of the POMC gene. Surprisingly, the POMC promoter lacks both cAMP‐responsive elements and Ca²⁺‐responsive elements through which the cAMP and Ca²⁺ signals could, in a relatively direct way, act on POMC gene expression. It is thus apparent that other, more indirect, mechanisms have evolved to utilize cAMP and Ca²⁺ signaling cascades to regulate POMC expression. This review gives an overview of the complex pathways and events that lead to the regulation of POMC gene expression in corticotrophs and melanotrophs. Another major site for POMC production is in hypothalamic neurons of the arcuate nucleus. In these neurons expression of the POMC gene relies on enhancer regions and responsive elements that differ from those utilized in the pituitary gland. In this review some attention will be given to progress made in unraveling the regulatory strategies acting on POMC expression in hypothalamic neurons. It is clear that the complexities of the promoter/enhancer structure of the POMC gene contribute to the versatility of this gene in participating in complex adaptation processes.