The small DNA tumor viruses encode proteins that subvert many of the pivotal growth regulatory pathways within the cell to facilitate their own replication. The cell responds to viral infection/proteins by activating the p53 tumor suppressor pathway. Activation of p53 could impair a productive viral infection at many levels, including the inhibition of viral DNA replication and/or the premature apoptosis of infected cells. Therefore, DNA viruses encode proteins that inactivate the p53 tumor suppressor pathway. Understanding how DNA viral proteins activate/inactivate the p53 pathway has provided invaluable insights into tumorigenesis. Recent studies with polyoma virus have identified a viral protein (PyST) that inhibits ARF-mediated activation of p53, and revealed a novel role for PP2A in the regulation of the ARF-p53 tumor suppressor pathway.