Surgery: Surgery, either by itself or used in combination with pre- and post-operative adjuvant therapies has proved unsuccessful. A pleurectomy/decortication is the most common surgery, in which the lining of the chest is removed. A less common surgery is an extrapleural pneumonectomy (EPP), in which the lung, lining of the inside of the chest, the hemi-diaphragm and the pericardium are removed.

Radiation: Radiation is often given post-operatively as a consolidative treatment for patients with localized disease who can tolerate a radical surgery. The entire hemi-thorax is treated with radiation therapy, often given at the same time as chemotherapy. Delivering radiation and chemotherapy after a radical surgery has led to extended life expectancy in selected patient populations with some patients surviving more than 5 years. As part of a curative approach to mesothelioma, radiotherapy is also commonly applied to the sites of chest drain insertion, in order to prevent growth of the tumor along the track in the chest wall.

Although mesothelioma is usually resistant to curative treatment with radiotherapy alone, palliative treatment regimens are sometimes used to relieve symptoms from tumor growth, such as obstruction of a major blood vessel. Radiation therapy, when given alone with curative intent, has never been shown to improve survival from mesothelioma.

Chemotherapy: As of February 2004, the United States Food and Drug Administration approved pemetrexed (brand name Alimta) for treatment of malignant pleural mesothelioma. Pemetrexed is given in combination with cisplatin. Folic acid is also used to reduce the side-effects of pemetrexed.

Immunotherapy: Treatment regimens involving immunotherapy have produced varied results.

Heated Intraoperative Intraperitoneal Chemotherapy: During heated intraoperative intraperitoneal chemotherapy, the surgeon removes as much of the tumor as possible and then directly administers a chemotherapy agent, heated to between 40 and 48°C, in the abdomen. The fluid is perfused for 60 to 120 minutes and then drained. This allows the administration of high concentrations of selected drugs into the abdominal and pelvic surfaces. Heating the chemotherapy treatment increases the penetration of the drugs into tissues. Heating itself damages the malignant cells more than the normal cells as well.