In this issue of the journal, Cramer and colleagues and Zhu and colleagues report carefully designed phase 3 assessments of candidate ovarian cancer screening biomarkers. The main conclusion is that CA-125 remains the "best of a bad lot"; the new candidates have fallen short of expectations. We review factors impeding the development of an effective ovarian cancer screening strategy, highlight the requirements related to validating proposed screening biomarkers, and emphasize the risks from premature clinical applications of unvalidated tests, all underscoring the need for new research strategies.