Despite improvements in median and overall survival using a combination of platinum and paclitaxel, long-term survival rates for patients with advanced epithelial ovarian carcinoma (EOC) remain disappointing, and the development of more effective primary therapies remains a priority. In particular, several nonplatinum agents have demonstrated activity in phase II trials among patients with recurrent platinum-resistant EOC. These agents include gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. Preclinical models have indicated a biologic basis for combinations of these agents with platinum, which has been attributed to inhibition of pathways involved in DNA repair. However, efforts to develop multidrug combinations with platinum and paclitaxel have encountered substantial bone marrow toxic effects, necessitating significant dose reductions and prompting exploration of alternative schedules and sequences of drug administration. In this regard, the Gynecologic Oncology Group (GOG) and other organizations have conducted pilot studies in previously untreated patients to define combinations that are suitable for group-wide phase III trials. With international collaboration, GOG has launched a five-arm trial that will compare four new combinations against carboplatin and paclitaxel. The selection of candidate regimens for this trial illustrates the challenges of drug development in EOC, emphasizing the role of phase II trials in patients with recurrent disease and indicating potential strategies to help evaluate newer biologic and molecular-targeted reagents.