The biological purpose of the mature, postthymic CD8(+) T cell is to respond to microbial antigens with a developmental program of clonal expansion and concomitant differentiation leading to effector cells (T(EFF)) that provide antimicrobial defense. Because many microbial infections persist into a chronic phase, this antigen-stimulated developmental program must be capable of continually generating T(EFF), perhaps for the lifetime of the individual. This chapter proposes that the ability of a CD8(+) T cell clone to maintain the continual production of T(EFF) during periods of persistent antigenic stimulation is based on a program that has two sequential phases of clonal expansion: an initial stage that occurs mainly in the secondary lymphoid tissues and is mediated by ligation of the T cell receptor (TCR) and CD27, and a subsequent, IL-2-dependent phase that occurs predominantly in peripheral, nonlymphoid tissues. The TCR/CD27-dependent phase establishes a nondifferentiating, self-renewing pool of clonally expanding cells, and the IL-2-dependent phase mediates continued clonal expansion that is coupled to the development of T(EFF). The two pools are linked by the process of asymmetrical division within the self-renewing subset so that, at steady state of cellular replication in this TCR/CD27-dependent subset, one daughter cell remains undifferentiated and the other initiates its commitment to IL-2-dependent terminal differentiation. Superimposed on this basic scheme are a shift in the CD8(+) T cell response to type I and II interferon (IFN) from anti- to pro-proliferative and transcriptional control of replicative senescence by Bmi-1, Blimp-1, and BCL6/BCL6b. This developmental program ensures that despite the occurrence of cellular senescence antiviral CD8(+) T cell clones are maintained for the duration of persistent viral infections.