Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor for which no effective therapy exists despite the discovery of many possible molecular and genetic targets. Many risk factors for MPM development have been recognized including environmental exposures, genetic susceptibility, viral contamination, and radiation. However, the late stage of MPM diagnosis and the long latency that exists between some exposures and diagnosis have made it difficult to comprehensively evaluate the role of risk factors and their downstream molecular effects. In this review, we discuss the current molecular and genetic contributors in MPM pathogenesis and the risk factors associated with these carcinogenic processes.