Studies of T-cell regeneration using animal models have consistently shown the importance of the thymus for T-cell regeneration. In humans, recent studies have shown that declines in thymic T-cell regenerative capacity begins relatively early in life, resulting in a limited capacity for T-cell regeneration by young adulthood. As a result, adult humans who experience profound T-cell depletion regenerate T cells primarily via relatively inefficient thymic-independent pathways, resulting in prolonged CD4 depletion, CD4+ and CD8+ subset alterations, limited TCR repertoire diversity and a propensity for activation induced cell death. These limitations in T-cell regeneration have significant clinical implications in the setting of HIV infection and bone marrow transplantation and may also contribute to immunologic abnormalities associated with normal aging. While the mechanisms responsible for thymic aging are not well understood, current evidence suggests that changes within the thymus itself are primary, while age-related changes in marrow T-cell progenitors and inhibitory factors within the extrathymic host milieu contribute to a lesser extent. The development of therapies which can reverse thymic aging are critical for improving outcome in clinical settings of T-cell depletion, and could potentially improve immunologic function in normal aged hosts.