Memory T lymphocytes proliferate in vivo in the absence of antigen maintaining a pool of central memory T cells (TCM) and effector memory T cells (TEM) with distinct effector function and homing capacity. We compared human CD4 naive T, TCM, and TEM cells for their capacity to proliferate in response to cytokines, that have been implicated in T cell homeostasis. Interleukin (IL)-7 and IL-15 expanded with very high efficiency TEM, while TCM were less responsive and naive T cells failed to respond. Dendritic cells (DCs) and DC-derived cytokines allowed naive T cells to proliferate selectively in response to IL-4, and potently boosted the response of TCM to IL-7 and IL-15 by increasing the expression of the IL-2/IL-15R and the common chain (c). The extracellular signal regulated kinase and the p38 mitogen-activated protein (MAP) kinases were selectively required for TCR and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures, some of the proliferating TCM differentiated to TEM-like cells acquiring effector function and switching chemokine receptor expression from CCR7 to CCR5. The sustained antigen-independent generation of TEM from a pool of TCM cells provides a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4 memory T cells.