Objective: Ovarian cancer, the deadliest of the gynecologic malignancies, poses a therapeutic challenge because of the 70% recurrence rate among patients treated with taxane/platinum-based chemotherapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer therapy due to its ability to selectively induce apoptosis in cancer cells with little toxicity to normal cells. Despite initially promising results from early TRAIL studies in ovarian cancer, reports of significant TRAIL resistance soon followed. The current study reviews strategies to overcome TRAIL resistance in ovarian cancer. Methods: PubMed was searched for published literature in English using key words "TRAIL," "ovarian," "death receptor" and "resistance". The references of identified articles were then searched for further related literature. Results: A number of mechanisms underlying TRAIL resistance have been proposed, including absence of death receptor expression and genetic alterations, leading to silencing of the downstream effects of ligand binding. Numerous strategies to overcome these mechanisms have been investigated, including combination treatment with cytotoxic chemotherapy, retinoids, proteasome inhibitors, demethylating agents, Akt inhibitors and EGFR inhibitors. Many of the combination treatments have demonstrated success at restoring TRAIL sensitivity in preclinical studies. Conclusion: Continued efforts with combination therapy designed to target multiple steps in apoptotic pathways may not only improve the efficacy of TRAIL-mediated therapies, but may also improve quality of life for ovarian cancer patients by reducing toxicity associated with cancer therapy. © 2010 Elsevier Inc.