Conducting clinical interventions in a research setting poses numerous challenges to clinicians, researchers, supervisors, and research participants. These issues often reflect a tension between the rigorous demands of a research protocol needed to ensure internal validity of the research and clinical flexibility that is representative of an externally valid intervention. In this paper, we explore difficulties in defining the roles of clinicians and research participants, delineating the scope of the intervention, and problems encountered at the intersection of clinical intervention delivery and such methodological techniques as randomization, blinding, and incentive payments. We provide guidance for setting frames for the intervention and clinical relationship, conducting training and supervision of clinical staff, and structuring quality-assurance procedures in order to meet these challenges.