Community health centers (CHCs) provide optimal research settings. They serve a high-risk, medically underserved population in the greatest need of intervention. Low socioeconomic status renders this population particularly vulnerable to research misconduct. Traditional principles of research ethics are often applied to participants only. The social-ecological model offers a comprehensive framework for applying these principles across multiple levels (participants, providers, organizations, communities, and policy). Our experience with the Trial Using Motivational Interviewing, Positive Affect and Self-Affirmation in African-Americans with Hypertension, a randomized trial conducted in CHCs, led us to propose a new platform for discussing research ethics; examine the social, community, and political factors surrounding research conducted in CHCs; and recommend how future research should be conducted in such settings.