Middle T antigen (MT) is the principal oncogene of murine polyomavirus. Its study has led to the discovery of the roles of tyrosine kinase and phosphoinositide 3-kinase (PI3K) signaling in mammalian growth control and transformation. MT is necessary for viral transformation in tissue culture cells and tumorigenesis in animals. When expressed alone as a transgene, MT causes tumors in a wide variety of tissues. It has no known catalytic activity, but rather acts by assembling cellular signal transduction molecules. Protein phosphatase 2A, protein tyrosine kinases of the src family, PI3K, phospholipase Cgamma1 as well as the Shc/Grb2 adaptors are all assembled on MT. Their activation sets off a series of signaling cascades. Analyses of virus mutants as well as transgenic animals have demonstrated that the effects of a given signal depend not only tissue type, but on the genetic background of the host animal. There remain many opportunities as we seek a full molecular understanding of MT and apply some of its lessons to human cancer.