Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are the principal C19 steroids produced by the human adrenals. Their plasma levels decline to less than 20% of their maximal value during aging. Because these steroids appear to play a role in the maintenance of immunity, musculoskeletal integrity, and cardiovascular health, age-associated declines in adrenal androgen production may contribute to decreased immune function, osteoporosis, and atherosclerosis. Production of DHEA and DHEAS has been localized to the zona reticularis (ZR) of the adrenal cortex and can be modulated by intra-adrenal or extra-adrenal modulators. Extra-adrenal modulators include corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), insulin, and transforming growth factor beta (TGF-beta). Intra-adrenal regulators include enzymes and proteins involved in the steroidogenic pathway, specifically 17,20 lyase activity and DHEA sulfotransferase (DST). The natural histories of the emergence of adrenal androgen production and the ontogeny of the ZR appear to correlate closely. In addition, aging results in a decline in adrenal androgen production, and our data suggest a parallel diminution in the area represented by the ZR. This decline in the ZR may result from apoptosis, cellular and humoral immunity, or a reduction in the replicative capacity of the cells of the ZR.