Malignant pleural mesothelioma continues to be a challenge. The diagnosis and treatment of patients with malignant pleural mesothelioma requires a multidisciplinary approach. The diagnosis is best made by thoracoscopic biopsy and the aid of immunohistochemistry. Molecular studies identified inactivation of the neurofibromatosis-2 gene and INK4alpha/ARF to be key events in tumorigenesis. Based on the results of a Phase III trial, the combination of cisplatin with pemetrexed has become the preferred choice for chemotherapy, although there is suggestive evidence for the activity of other platin combinations based on Phase II studies. The optimal second-line chemotherapy remains to be defined. Surgical interventions ranging from pleurectomy/decortication to extrapleural pneumonectomy are increasingly offered in specialized centers, and the results of multimodality approaches with neoadjuvant or adjuvant chemotherapy and extrapleural pneumonectomy are encouraging. Ongoing investigations are defining the role of postoperative radiotherapy and the clinical activity of tyrosine kinase inhibitors targeting VEGFR2, histone deacetylase inhibitors and proteosome inhibitors.