Survival of all living organisms depends on maintenance of a steady state of homeostasis, which process relies on its ability to react and adapt to various physical and emotional threats. The defense against stress is executed by the hypothalamic–pituitary–adrenal axis and the sympathetic–adrenal medullary system. Adrenal gland is a major effector organ of stress system. During stress, adrenal gland rapidly responds with increased secretion of glucocorticoids (GCs) and catecholamines into circulation, which hormones, in turn, affect metabolism, to provide acutely energy, vasculature to increase blood pressure, and the immune system to prevent it from extensive activation. Sepsis resulting from microbial infections is a sustained and extreme example of stress situation. In many critical ill patients, levels of both corticotropin-releasing hormone and adrenocorticotropin, the two major regulators of adrenal hormone production, are suppressed. Levels of GCs, however, remain normal or are elevated in these patients, suggesting a shift from central to local intra-adrenal regulation of adrenal stress response. Among many mechanisms potentially involved in this process, reduced GC metabolism and activation of intra-adrenal cellular systems composed of adrenocortical and adrenomedullary cells, endothelial cells, and resident and recruited immune cells play a key role. Hence, dysregulated function of any of these cells and cellular compartments can ultimately affect adrenal stress response. The purpose of this mini review is to highlight recent insights into our understanding of the adrenal gland microenvironment and its role in coordination of stress-induced hormone secretion.