Summary: Human viruses elicit functionally highly diverse CD8+ T-cell responses. This variation, which manifests in the memory or latency stage, includes differences in expansion requirements, migratory properties, homeostatic maintenance mechanisms, and constitutive effector properties, and it may reflect specific adaptations of the human immune system to challenges posed by individual pathogens. Longitudinal follow-up of individuals after primary virus infections has revealed how divergent virus-specific CD8+ T cells may develop from the initially expanded virus-specific T-cell effector pool. Recent findings have shown that CD8+ T cells reactive toward latent viruses may depend on other mechanisms for their homeostatic maintenance than T cells specific for cleared viruses. Whereas the latter can respond to the homeostatic cytokine interleukin-7 (IL-7), many persistent virus-specific T cells, recognizing latent herpesviruses such as Epstein–Barr virus and cytomegalovirus (CMV), lack IL-7 receptor α (IL-7Rα) and depend on viral antigens to persist. Finally, CMV is unique in that it generates a vast pool of resting virus-specific T cells with constitutive cytolytic effector function. The putative role of functionally diverse CD8+ T cells in protective immunity to persistent viruses is discussed in this review.