Malignant pleural mesothelioma (MPM) is a highly severe primary tumor of the pleura mainly related to exposure to asbestos fibers. The median survival after symptom onset is less than 12 months. Conventional medical and surgical therapies--either as single lines or combined--are not wholly effective. No universally accepted guidelines have yet been established for patient selection and the use of therapeutic strategies. In addition, retrospective staging systems have proved inadequate at improving therapeutic outcomes. Therapy is currently guided by gross tumor characteristics and patient features; however, these seem less accurate than the biological fingerprint of the tumor. A number of clinical prognostic factors have been considered in large multicenter series and independently validated. A series of novel biomarkers can predict the evolution of the disease. Here we summarize the principal and novel factors that influence prognosis and are thus potentially useful for selecting patients for targeted therapy.