The receptor tyrosine phosphatase CD45 is expressed on the surface of almost all cells of hematopoietic origin. CD45 functions are central to the development of T cells and determine the threshold at which T and B lymphocytes can become activated. Given this pivotal role of CD45 in the immune system, it is probably not surprising that viruses interfere with the activity of CD45 in lymphocytes to dampen the immune response and that they also utilize this molecule to accomplish their replication cycle. Here we report what is known about the interaction of viral proteins with CD45. Moreover, we debate putative interactions of viruses with CD45 in myeloid cells and the resulting consequences—subjects that remain to be investigated. Finally, we summarize the evidence that pathogens were the driving force for the evolution of CD45.