Malignant pleural mesothelioma is a highly invasive tumor arising from the mesothelial cells of serosal surfaces. Several chemotherapeutic agents have been tested for the treatment of this disease and doublet cisplatin with antifolates has been demonstrated to have significant efficacy in Phase III studies. However, the benefit of these treatments remains poor and the median survival time of patients is low, ranging between 9 and 17 months. Targeted therapies are being developed in oncology and emerging evidence suggests that they offer disease control in several tumors. This article reviews the knowledge on the malignant pleural mesothelioma molecular pathway and focuses on results of clinical trials conducted on this devastating disease.