To overcome the significant mortality associated with ovarian cancer, a highly sensitive and specific screening test is urgently needed. CA-125 testing is used to monitor response to chemotherapy, detect recurrence, and detect late stage ovarian cancer. However, CA-125 testing, alone or in combination with ultrasonography, has not been adequate for early detection of ovarian cancer. This article discusses the authors' recent report of a novel multiplex assay that uses a panel of six serum biomarkers: leptin, prolactin, osteopontin, insulin-like growth factor II (IGF-II), macrophage inhibitory factor (MIF), and CA-125. The combination of these six proteins yielded 95.3% sensitivity and 99.4% specificity. The application of this test in the clinical context and the most appropriate population, which could benefit from the test, are discussed.