Mesothelioma is a rare malignancy of the pleura with limited therapeutic options. Despite the desperate need to develop better treatment for this disease, the rarity of the tumor type creates formidable challenges in clinical research. Nonetheless, several novel agents are under investigation. Most efforts are directed toward improving standard first-line therapy with pemetrexed and cisplatin, or developing effective second-line treatments. Several classes of drugs are being explored, including those that impact DNA transcription, cell-cycle progression, angiogenesis, and immune tolerance. This article describes several ongoing or recently completed phase II and III trials using novel agents vorinostat, everolimus, CBP501, MORAb-009, NGR-hTNF, WT1 vaccine, bevacizumab, cediranib, and thalidomide.