Malignant pleural mesothelioma (MPM) results from the neoplastic transformation of pleural mesothelial cells. Asbestos exposure is a major risk factor for MPM, but epidemiologic studies demonstrated the occurrence of MPM in populations exposed to other fibers, and an excess of MPM in populations occupationally exposed to man-made vitreous fibers and previously to asbestos. The development of nanotechnologies also raises some concern about the potential health effects of new particles of high aspect ration, such as carbon nanotubes. Toxicological studies investigated the mechanism of asbestos-induced transformation of mesothelial cells, and molecular analyses defined the genomic and physiopathological changes in MPM. These findings allowed identifying some key events accounting for the neoplastic process. This article summarizes the known and suspected causes of MPM, the cellular events and responses of mesothelial cells to asbestos fibers and the alterations of key genes and regulatory pathways involved in the pathological mechanism.