Three major subsets of antigen-experienced T cells have been identified based on surface markers and distinct functional properties: short-lived effector T cells, central memory T cells and effector memory T cells. The precise relationship among these subsets and their mode of differentiation are still controversial. Recent studies, however, have provided compelling evidence for an early delineation of the effector versus memory T-cell fates regulated through specific transcription factors. Cytokines have long been recognized as being important for the shaping of a T-cell response and for the maintenance of memory T cells. The observation that short-lived effector and memory T cells, as well as their precursors, express distinct levels of IL7R has provided an important tool to examine the role that cytokines play in the programming of T-cell differentiation pathways and of the transcriptional regulators that guide these processes. IL2 and IL12 in particular have been shown to provide the signals that induce or repress transcription factors, such as T-bet, Eomes and Blimp-1, all of which are crucial in the differentiation and homoeostasis of effector and memory T cells. The coordinated differentiation of a heterogeneous population of antigen-specific T cells early during an immune response is essential for the effective eradication of pathogens and the long-term protection against reinfection. Thus, understanding the signals and transcriptional programmes in T-cell differentiation is a key to successful manipulation of T-cell responses during vaccination.