The incidence of mesothelioma has gone from almost none to the current 2500-3000 cases per year in the USA. This estimate is an extrapolation based on information available from the Surveillance, Epidemiology and End Results (SEER) Program that collects information on approximately 12% of the US population. Mesothelioma is a cancer that is linked to exposure to carcinogenic mineral fibers. Asbestos and erionite have a proven causative role; the possible role of other mineral fibers in causing mesothelioma is being investigated. Asbestos is considered the main cause of mesothelioma in the US and in the Western world. The capacity of asbestos to induce mesothelioma has been linked to its ability to cause the release of TNF-alpha (that promotes mesothelial cells survival), other cytokines and growth factors, and of mutagenic oxygen radicals from exposed mesothelial cells and nearby macrophages. Some investigators proposed that as a consequence of the regulations to prevent exposure and to forbid and/or limit the use of asbestos, the incidence of mesothelioma in the US (and in some European countries) should have started to decline before or around the year 2000, and sharply decline thereafter. Unfortunately, there are no data available yet to support this optimistic hypothesis. Simian virus 40 (SV40) infection and radiation exposure are additional causes, although their contribution to the overall incidence of mesothelioma is unknown. Recent data from several laboratories indicate that asbestos exposure and SV40 infection are co-carcinogens in causing mesothelioma in rodents and in causing malignant transformation of human mesothelial cells in tissue culture. An exciting new development comes from the discovery that genetic susceptibility to mineral fiber carcinogenesis plays a critical role in the incidence of this cancer in certain families. It is hoped that the identification of this putative mesothelioma gene will lead to novel mechanistically driven preventive and therapeutic approaches.