A major challenge in the conduct of clinical trials is recruiting and retaining adequate numbers of study participants. Pressure for steady recruitment and retention is great. A wide range of strategies are used to retain participants; however, some approaches raise ethical questions. This article examines issues of participant retention, literature addressing the volunteer nature of informed consent, the moral distress surrounding participant withdrawal, and potential ethical implications. Strategies are proposed to resolve issues and reduce participant and investigator distress. Case studies of two patients with complex chronic illnesses illustrate practical solutions and lessons learned.