Loss of existing T cell populations is a significant clinical problem following cytoreductive therapies or in disease states such as HIV. Characterization of the pathways of T cell regeneration, their limitations and regulation, is central to the development of new approaches for the correction of T cell lymphopenia. Recently, there has been an increasing appreciation that subsets of T cells differ not only in requirements for homeostasis, but in the mechanisms of initial generation and later reconstitution of lost populations. In this issue, Cox et al. determine that variations in cytokine/chemokine levels may affect the biology of T cell recovery which impacts on the development of treatment strategies for lymphopenia.