The large tumor antigen (T antigen) of simian virus 40 is necessary and sufficient for the neoplastic transformation of a number of established cell lines. Mutational analysis has revealed that a biochemical activity residing within the amino-terminal 121 amino acids of T antigen is sufficient to induce the transformation of some cell lines, such as C3H10T1/2. The same domain of the molecule also encodes the transactivation function of T antigen and the ability to complex with the retinoblastoma susceptibility gene product. However, the transformation of other lines, such as REF52, requires an additional activity that is affected by mutations in other portions of the molecule.