Because oncogenic DNA viruses establish persistent infections in humans, continuous immunosurveillance for neoplastic cells is required to prevent virus-induced tumors. Antigen-specific CD8+ T lymphocytes are critical in vivo effectors for eliminating virus-infected and virus-transformed cells. Investigation into the induction, regulation, and maintenance of CD8+ T cells specific for these viruses is hindered by the lack of tractable animal models that mimic natural infection. Resistance to tumors induced by polyoma virus, a persistent natural mouse DNA virus, is mediated by polyoma-specific CD8+ T cells. Mice susceptible to polyoma virus tumorigenesis mount a smaller, albeit still considerable, expansion of anti-polyoma CD8+ T cells; importantly, these antiviral CD8+ T cells lack cytotoxic activity while retaining the phenotype of cytotoxic T lymphocyte (CTL) effectors. In this review, we will discuss potential in vivo mechanisms that regulate the functional competence of anti-polyoma CD8+ T cells, particularly in the context of chronic antigenic stimulation provided by persistent viral infections and tumors.