Mesothelioma is one of the most aggressive human cancers and kills approximately 2500 people per year in the US. This cancer was almost unknown until the second half of the 20th century, and its rapid increase has been linked to the widespread use of asbestos. In spite of an enormous research effort, the mechanisms of asbestos carcinogenicity have remained an enigma. Why only a fraction of individuals exposed to high levels of asbestos develop mesothelioma while individuals with low to no asbestos exposure also develop this cancer remains unknown. Recently, simian virus 40, a DNA tumor virus known to preferentially cause mesotheliomas in hamsters, and genetic factors have been linked to mesothelioma development. Therefore, a new research front has been opened in mesothelioma, a cancer that appears to be caused by the environmental carcinogens asbestos and erionite, viruses, and genetic predisposition. The challenge for future research is to establish how these apparently very different factors interact to cause mesotheliomas.