In 1898, Friedrich Loeffler and Paul Frosch reported on the identification of a filterable agent that was the cause of foot and mouth disease in livestock (Levine 2001). This was the first identification of a vertebrate virus, shortly after the isolation of the tobacco mosaic virus by Dimitrii Ivanovsky in 1892 (Horzinek 1997). Since these initial discoveries, we have come to appreciate how these genetic entities that lie somewhere between the living and nonliving state survive, propagate, infect, and mediate disease. We know that in the absence of a host cell, these obligate parasites exist in a latent form containing a protein or membrane coat surrounding genetic material that encodes protein products that are essential for host infection and propagation of the virus. Upon contact with its host cell, the virus injects its genetic material to exploit the host cellular machinery to assemble more virus particles that eventually go on to infect other host cells. We also know that many viruses are the causative agents for human diseases such as smallpox, influenza, the common cold, AIDS, and cervical cancer. We know considerably less about the molecular mechanisms for how viral proteins subvert the host machinery to establish the disease state. A study in this issue of Genes & Development by Lilyestrom et al.(2006) reports on a crystal structure of the simian virus 40 (SV40) large T-antigen (LTag) bound to the human p53 protein, a target that is also inactivated in the majority of human cancers. The study provides the first molecular insights into the mode of viral inactivation of this “guardian of the genome” and suggests avenues for the structure-based design of viral inhibitors (Weinberg 1997; O’Shea 2005)