PURPOSE: Establishing content validity for both new and existing patient-reported outcome (PRO) measures is central to a scientifically sound instrument development process. Methodological and logistical issues present a challenge in regard to determining the best practices for establishing content validity. METHODS: This paper provides an overview of the current state of knowledge regarding qualitative research to establish content validity based on the scientific methodological literature and authors' experience. RESULTS: Conceptual issues and frameworks for qualitative interview research, developing the interview discussion guide, reaching saturation, analysis of data, developing a theoretical model, item generation and cognitive debriefing are presented. Suggestions are offered for dealing with logistical issues regarding facilitator qualifications, ethics approval, sample recruitment, group logistics, taping and transcribing interviews, honoraria and documenting content validity. CONCLUSIONS: It is hoped this paper will stimulate further discussion regarding best practices for establishing content validity so that, as the PRO field moves forward, qualitative research can be evaluated for quality and acceptability according to scientifically established principles.