Because virus infections elicit various cellular responses that inhibit viral replication and growth, viruses must intervene to attenuate antiviral measures in order to thrive. The genome guardian p53 plays a central part not only in DNA damage responses, inducing cell cycle arrest or apoptosis, but also in the innate host immune control of viral infections by orchestrating diverse signaling pathways originating from many different cellular receptors and sensors. Many viruses have acquired sophisticated mechanisms to regulate p53 functions by deploying subversive proteins and modulating its post-transcriptional status. In this review, we overview the mechanisms by which DNA and RNA viruses manage p53 signaling in favor of their continued survival. Copyright © 2012 John Wiley & Sons, Ltd.