We reviewed the published literature of clinical studies in malignant mesothelioma (MM), including phase II as well as older single-agent and combination chemotherapy trials with more than 15 patients. While response rates exceeding 30% have been achieved with established cytotoxic drugs in MM therapy, novel chemotherapeutic agents and their combinations appear more promising. This applies especially to the anti-metabolites (i.e. pemetrexed) that produced response rates of up to 45% in combination with platinum compounds. Moreover, agents targeting novel proliferative and survival pathways in MM are developed to improve treatment outcomes. Here, we focused on the role of several angiogenic growth factors in MM biology and the data of MM-oriented studies on angiostatic agents tested in a phase I-II trial. It seems likely that no single treatment modality will be effective by itself. Studies that use combinations of the newer agents, including angiostatic drugs, with chemotherapy, should be conducted.