Neuroendocrine structures integrate a vast range of external cues and internal signals that, in turn, result in adaptive physiological responses. Emerging data indicate that light, social cues, stress and energy balance stimulate relatively short- as well as long-term genomic modifications in discrete neuroendocrine structures, which are mediated by epigenetic mechanisms. Moreover, environmentally-induced fluctuations in the synthesis of local hypothalamic and circulating hormones provide an internal signal that contributes to the extensive neuroendocrine genomic plasticity. This review examines the impact of environmental stimuli and endogenous hormonal signals on the regulation of epigenetic enzymes in key neuroendocrine structures. The data discussed are predominantly derived from studies in the neuroendocrine control of seasonal reproduction and the impact of social stress in rodent models. The perspective presented considers the role of estrogen and glucocorticoids as the primary catalysts for inducing epigenetic modifications (e.g., DNA methylation) in specific neuroendocrine structures. Estrogen and glucocorticoid actions suggest: 1) a preferential action for specific epigenetic enzymes and 2) nucleus- and cell-specific modifications. Untangling the complex web of hormonal regulation of methylation and acetylation will enhance our understanding of short- and long-term changes in epigenetic enzymes that generate adaptive and pathological neuroendocrine responses.