Malignant pleural mesothelioma (MPM), arises from the mesothelial cells, is difficult to be diagnosed at an early stage, and is refractory to conventional chemotherapy and radiotherapy. Therefore, the establishment of novel effective therapies is necessary to improve the prognosis for many patients with this disease. Recent studies have demonstrated that angiogenesis plays a significant role in MPM progression, suggesting the importance of tumor vessels as therapeutic targets. To explore molecular pathogenesis and evaluate the efficacy of vascular targeting therapy in MPM, we developed orthotopic implantation SCID mouse models of MPM. We found that selective VEGF inhibitors were effective only in the treatment of high-VEGF-producing MPM models. On the other hand, multiple kinase inhibitor E7080, with inhibitory activity against various angiogenic cytokine receptors, suppressed the progression and prolonged survival of both high-VEGF-producing and low-VEGF-producing MPM models. Further understanding of the functional characteristics of tumor angiogenesis may be essential to improve targeting therapies in MPM. In this review, we introduce current status of clinical strategies and novel therapeutic approaches against angiogenesis in MPM.