A decline in the human immune system that occurs with aging is known as immunosenescence. Several factors are involved in the process, including reduced neutrophil function and cytotoxic capacity of natural killer (NK) cells, thymus atrophy and reduced naïve T cell number, and lowered B cell antibody production in response to antigen. The endocrine system, specifically the hypothalamus-pituitary-adrenal axis, plays an important role in modulating immune function. With aging an imbalance occurs between two adrenal hormones, cortisol and DHEA, that have opposing actions on immune function. This brief review explores the interactions between cortisol and DHEA and their effects on immune function in aging, as well as potential methods to combat the endocrine-related contribution to immunosenescence, including DHEA supplementation and exercise. © 2008 NRC.