The diagnosis and management of malignant pleural mesothelioma are major challenges that often frustrate both patient and clinician alike. Occupational asbestos exposure to crocidolite or amosite forms of the fiber is the most important known risk factor in North America and Western Europe. Other mineral fibers such as erionite, a naturally occurring fibrous zeolite crystal, are associated with mesothelioma in volcanic tuffs of the Cappadocia region of central Anatolia in Turkey. In addition, other possible factors such as the presence of simian virus 40 and genetic susceptibility have been associated recently with the development of mesothelioma in animal models. These latter findings are increasing our understanding of this disease. In addition, the discovery of elevated levels of various markers such as folic acid receptor α, cyclooxygenase 2, and multidrug resistance proteins 1 and 2 in mesothelioma tissue have opened up new areas of potential diagnostic and therapeutic importance. However, traditional treatment modalities—surgery, radiotherapy, and chemotherapy—have evolved slowly, and few gains in therapeutic efficacy have occurred. Recently, however, continuing research efforts have led to novel treatment strategies that are changing the way clinicians view a disease that has traditionally been managed with almost universal therapeutic nihilism. This review explores our current knowledge of this disease and presents current and novel therapeutic strategies.