Novel targeted therapies have found a niche in the treatment of many cancers, although the most responsive populations, best biomarkers of response, and appropriate treatment settings are still under investigation. With few exceptions, cancer vaccination strategies have not entered into routine management. In malignant mesothelioma, combination first-line chemotherapy with a platinum and pemetrexed remains the standard of care when systemic therapy is considered. Second-line chemotherapy is used but benefits are uncertain in the absence of appropriately controlled randomized trials. Currently, there are no novel targeted therapies or vaccinations that should be used in this disease outside the context of a clinical trial.