Malignant pleural mesothelioma is a rare primary tumor rising from the pleura and is associated with exposure to asbestos fibers. Mesothelioma is a locally aggressive disease that usually presents at an advanced stage and has a median overall survival of 1 year. Treatment options rarely result in cure of disease and range from trimodality treatment, including chemotherapy, radiation, and surgery, to supportive care. In patients with limited local disease and good functional status, trimodality treatment with extra-pleural pneumonectomy, chemotherapy, and radiation is frequently employed. Best supportive care should be instituted for patients with metastatic disease and poor functional status. Palliative therapy focuses on control of pleural effusions with drainage techniques and pain with radiation therapy. Novel therapies are showing promise, including photodynamic therapy, immunotherapy, and molecular targeted therapy.