The CD8+ T cell response to infection is characterized by the appearance of short-lived (CD127 low killer cell lectin-like receptor G 1–high) and memory-precursor (CD127 high killer cell lectin-like receptor G 1–low) effector cells. How and when central-memory T (T CM; CD62L high CCR7+) cell and effector-memory T (T EM; CD62L low CCR7−) cell subsets are established remains unclear. We now show that the T CM cell lineage represents an early developmental branchpoint during the CD8+ T cell response to infection. Central-memory CD8+ T cells could be identified prior to the peak of the CD8+ T cell response and were enriched in lymphoid organs. Moreover, the kinetics and magnitude of T CM cell development were dependent on the infectious agent. Furthermore, the extent of early Ag availability, which regulated programmed death-1 and CD25 expression levels, controlled the T CM/T EM cell lineage decision ultimately through IL-2 and IL-15 signaling levels. These observations identify key early signals that help establish the T CM/T EM cell dichotomy and provide the means to manipulate memory lineage choices.