Mesotheliomas are malignant tumors usually associated with occupational asbestos exposure. Simian virus 40 (SV40) is a DNA tumor virus that preferentially causes mesotheliomas when injected intracardially and/or intrapleurally into hamsters. SV40 also transforms human cells in tissue culture, and these cells contain extensive DNA damage. In the United States, at least 60% of human mesotheliomas contain and express SV40. In these tumor cells, the SV40 tumor antigen binds and inhibits the cellular tumor suppressors p53 and Rb. These findings suggest that SV40 may contribute to the development of those human mesotheliomas that occur in people not exposed to asbestos. SV40 may also facilitate asbestos-mediated carcinogenicity. The epidemiological data available are insufficient to address the role that SV40 may have played in contributing to the increased incidence of mesothelioma in the second half of this century.