The immune system undergoes dramatic changes with age-the thymus involutes, particularly from puberty, with the gradual loss of newly produced naïve T cells resulting in a restricted T cell receptor repertoire, skewed towards memory cells. Coupled with a similar, though less dramatic age-linked decline in bone marrow function, this translates to a reduction in immune responsiveness and has important clinical implications particularly in immune reconstitution following cytoablation regimes for cancer treatment or following severe viral infections such as HIV. Given that long-term reconstitution of the immune system is dependent on the bi-directional interplay between primary lymphoid organ stromal cells and the progenitors whose downstream differentiation they direct, regeneration of the thymus is fundamental to developing new strategies for the clinical management of many major diseases of immunological origin. This review will discuss the impact of aging on primary lymphoid organ niches and current approaches for thymic regeneration and immune reconstitution.