The few long-term survivors of MPM have been cured with radical surgical extirpation often followed by radiation therapy and adjuvant chemotherapy. The combination of pemetrexed and cisplatin recently was shown to improve survival over treatment with cisplatin alone. Given the size and robustness of that trial, the combination should be the new standard treatment for this cancer. Combined modality approaches to therapy, including surgery, radiation, and chemotherapy, are becoming the standard of care in patients with resectable mesothelioma. Two phase II studies have demonstrated that neoadjuvant chemotherapy is safe and apparently effective. A third phase II trial will use the combination of pemetrexed plus cisplatin preoperatively followed by surgery and radiation for patients with T1-3 N0-2 mesothelioma. If the statistical analysis of this study shows a measurable pathologic complete response rate and a median survival that exceeds the current expected value of 20 to 24 months, a phase III trial comparing surgery and radiation to surgery, radiation, and chemotherapy will be considered.