As the key integrator of nuclear structure and function, the nuclear matrix is likely to be an important target for structural and functional alterations during the process of neoplastic transformation. Here I summarize and discuss data demonstrating that the major transforming protein of the small DNA tumor virus simian virus 40 (SV40), the SV40 large tumor antigen (large T), specifically targets the chromatin and the nuclear matrix during viral transformation. I then turn to recent evidence endorsing the concept that mutant p53 — the most commonly expressed oncogene in human cancer — might exert its oncogenic activities by specifically interacting with the nuclear matrix. The data suggest that SV40 large T and mutant p53 might be members of a new family of oncogenes that exert their oncogenic functions by directly modulating nuclear structure and function.