Systemic therapy options for patients with mesothelioma remain limited. Although many conventional chemotherapeutic agents have shown modest activity in this disease, only the combination of cisplatin plus pemetrexed has demonstrated an improvement in clinical outcomes in a phase III trial when compared with single modality therapies. Clinical investigations of the use of targeted therapies in mesothelioma are ongoing, as investigators attempt to inhibit critical pathways in this disease. This article surveys the current clinical landscape of systemic therapies in mesothelioma and explores the impact of both conventional and targeted agents.