Content validity of patient-reported outcome measures (PROs) has been a focus of debate since the 2006 publication of the U.S. FDA Draft Guidance for Industry in Patient Reported Outcome Measurement. Under the auspices of the Patient Reported Outcomes Measurement Information System (PROMIS) initiative, a working meeting on content validity was convened with leading PRO measurement experts. Platform presentations and participant discussion highlighted key issues in the content validity debate, including inconsistency in the definition and evaluation of content validity, the need for empirical research to support methodological approaches to the evaluation of content validity, and concerns that continual re-evaluation of content validity slows the pace of science and leads to the proliferation of study-specific PROs. We advocate an approach to the evaluation of content validity, which includes meticulously documented qualitative and advanced quantitative methods. To advance the science of content validity in PROs, we recommend (1) development of a consensus definition of content validity; (2) development of content validity guidelines that delineate the role of qualitative and quantitative methods and the integration of multiple perspectives; (3) empirical evaluation of generalizability of content validity across applications; and (4) use of generic measures as the foundation for PROs assessment.