Summary: Clones of CD8+ T cells that have been selected in the primary response must have a mechanism by which they can continuously or intermittently generate new effector cells. Several years ago, this mechanism was proposed to involve a self-renewing, stem cell-like subset that could avoid the differentiating effects of interleukin-2 (IL-2). The model considered the stem cell subset to be contained within the central memory population of CD8+ T cells (TCM). This proposal was inconsistent with subsequent findings suggesting that all antigen-activated CD8+ T cells differentiated to effector cells (TEFF) during the primary response and that TCM developed during the memory phase by de-differentiating from effector memory cells (TEM). However, findings have since been reported that support the stem cell model. First, studies indicate that TEM do not serve as the precursors of TCM. Second, transcriptional repressors of IL-2 signaling do enhance the memory response. Third, memory cells lacking effector functions and with a capacity to replicate in a secondary response develop in the absence of signaling through the IL-2/IL-15 receptor. Taken together, these findings suggest that antigen-activated CD8+ T cells with a stem cell-like capability for maintaining proliferative potential develop by an unknown IL-2-independent process. The challenge is now to identify this unknown pathway of clonal expansion.