SV40 LT and ST antigens cooperate to induce the proliferation and eventual transformation of several human cell types. In natural virus infections, ST often enhances the function of LT when both proteins are present, and it can be difficult to completely separate the roles of the individual proteins. By studying ST in the absence of LT or by replacing ST function with combinations of cellular proteins, several themes have emerged which help define the requirement for ST in human cell transformation. These include the activation of transcription of two cyclins, D and A, along with downregulation of the cyclin kinase inhibitor p27. Modification of these key cell cycle regulators may be influenced by the activation of key downstream targets in the PI3K pathway.