Summary: During T-cell priming, cytokines and costimulatory molecules provide important signals that determine the magnitude and quality of the response. Although the functions of defined cytokines and costimulators in the primary T-cell response are well characterized, much less is known about how these factors contribute to memory T-cell development and survival. Since memory cells are thought to be long-lived progeny of the primary response, it is conceivable that the same signals shaping initial T-cell expansion and differentiation also contribute to memory generation. Here, we review evidence and show novel data on the role of the cytokines interleukin-2 (IL-2) and IL-7 and the costimulator CD28 in CD4+ memory T-cell development. We emphasize that transient IL-2 and CD28 signals during priming imprint a long-lasting survival advantage in primed T cells, thus contributing to the persistence of a memory population. The requirement for IL-2 and CD28 signals is not linked to promoting T-cell division and expansion but most likely due to their capacity to (i) promote effector cell differentiation; (ii) induce survival proteins, and, as we discuss in more detail; (iii) program expression of receptors for ‘memory survival factors’ such as IL-7. Studies exploring the therapeutic potential of these insights are also discussed.