Abstract: The thymus involutes relatively early in life; cellular immune deficiencies of aging correspond to decline in function of the hypothalamic-pituitary-endocrine axis. Recent studies point to important roles for the pituitary, the pineal, and the autonomic nervous system as well as the thyroid, gonads and adrenals in the thymus integrity and function. Thymic function at the local level requires complex cellular interactions among thymic stromal cells and developing thymocytes involving paracrine and autocrine mediators including interleukins (ILs) 1, 2, 6, 7, 8, colony-stimulating factors (CSFs), interferon-γ, thymosin α1, and zinc-thymulin. An important endocrine function of the thymus is to package zinc in zinc-thymulin for delivery to the periphery. Thymic involution has been treated with interleukins, thymic hormones, growth hormone, prolactin, melatonin, zinc, and others. Our work to reverse thymic involution in hydrocortisone-treated, aged mice with interleukins, thymosin α1, and zinc will be reviewed. Recent efforts to treat successfully immune deficiency in aged and cancer-bearing humans will be presented.