Malignant mesothelioma is a relatively rare tumor, but the incidence of the disease appears to be increasing. Unique molecular changes are associated with the disease that distinguish it from lung cancers. Smoking is not an etiologic factor; the major causative agent is asbestos exposure, usually many years or decades before the development of the tumor. Recently, a simian virus, SV40, has been associated with malignant mesotheliomas and is a probable cofactor in tumor development. The molecular changes caused by each of these major etiologic factors and their interrelationships are the focus of this review.