The thymus is primarily responsible for T cell production. However, it begins to recede in size and function, from early in life. This decreased generation of naive T cells during normal thymus ageing, or linked with pathology (i.e. chronic inflammation), leads to reduced T cell specificities, peripheral T cell imbalances, and higher susceptibilities to infections. Various clinical strategies for thymus and T cell recovery have been investigated, although no effective clinical treatments for the reconstitution of peripheral T cell diversity in severe immune deficiencies are available. The recent identification of thymic epithelial progenitor cells (TEPC) in the adult thymus will enable investigations into a new generation of therapies focused on regenerating the thymic microenvironment for diverse specificity T cell reconstitution in the elderly. The specific mechanisms underlying TEPC activation are still being investigated. Recent data point to an important role of the intrathymic transforming growth factor-β (TGF-β) circuitry. Although dual actions of this cytokine have been reported in the immune system, TGF-β signaling is transiently activated in hematopoietic stem and progenitor cells during hematopoietic regeneration. This review investigates the current strategies for thymus reactivation to replenish the peripheral T cell repertoire and potentially reverse the age-related inflammatory milieu.