Chemotherapy of malignant mesothelioma is of great importance because most patients with malignant pleural mesothelioma are diagnosed for the first time with widespread or advanced disease. Due to the small number of patients in clinical trials and due to difficulties in tumour assessment in the last 20 years, validation criteria for efficacy could only be defined with major limitations. After the introduction of modern antifolates in the chemotherapy for malignant mesothelioma and after the establishment of standardised response criteria, a significant prolongation of survival time by combination chemotherapy was shown in two randomised phase III trials. The combination of pemetrexed and cisplatin is the current standard of chemotherapy in malignant mesothelioma. Besides first-line therapy, there are also data to support the efficacy of chemotherapy in pretreated patients. In spite of the various results of preclinical trials which support the prognostic significance of certain targeted structures of intra- and intercellular signal transduction, no relevant efficacy could be shown for targeted therapies in mesothelioma up to now.