The current treatment of choice of epithelial ovarian cancer involves aggressive tumor cytoreductive surgery followed by platinum- and taxane-based chemotherapy; however, despite the encouraging activity of these agents, most ovarian carcinomas relapse and many patients die from drug-resistant disease. After the failure of platinum- and taxane-based schedules, several cytotoxic agents have demonstrated activity in advanced ovarian cancer but none were able to induce significant and durable responses. Among the new cytotoxic agents, pemetrexed plays an emerging role in different tumors, demonstrating competitive activity and a promising safety profile. In ovarian cancer, pemetrexed has been investigated, with encouraging results, as a single agent and in association with platinum compounds; moreover, the drug has shown interesting activity both in platinum-sensitive and platinum-resistant ovarian cancer. According to these clinical results it appears reasonable to explore the combination of pemetrexed with other cytotoxic agents and also with targeted therapies in relapsed ovarian cancer patients.