Polyomaviruses establish persistent infection in a variety of hosts, including humans, where they pose an oncogenic threat under conditions of depressed immune function. Control of persistent infection by these DNA tumor viruses requires continuous immunosurveillance by functionally competent antiviral CD8+ T cells. Repetitive antigen encounter by these T cells, however, often leads to their deletion or inactivation. Elucidation of the in vivo mechanisms that sustain antigen-specific CD8+ T-cell effector activity in the face of persistent antigen is essential for devising immunotherapeutic strategies against viral oncogenesis.