Cancer is thought to arise as a consequence of multiple insults to a cell. Mutations that lead to increased expression or activity of proto-oncogenes or decreased expression of tumor suppressors are common insults that have been identified to date. However, when considering tumor viruses, viral proteins that modify cellular gene expression, alter host immune surveillance, or affect signaling pathways are also common players. Notably, several of these tumor viruses encode proteins containing an immunoreceptor-associated tyrosine-based activation motif (ITAM), a signaling motif recently implicated in epithelial cell oncogenesis. As expression of proteins bearing this motif is normally restricted to hematopoietic cells, recent work highlighting the consequences of ITAM expression in epithelial cells suggests it may play a role in solid tumor formation.