Presently, health care simulation research is largely conducted on a study-by-study basis. Although such "project-based" research generates a plethora of evidence, it can be chaotic and contradictory. A move toward sustained, thematic, theory-based programs of research is necessary to advance knowledge in the field. Recognizing that simulation is a complex intervention, we present a framework for developing research programs in simulation-based education adapted from the Medical Research Council (MRC) guidance. This framework calls for an iterative approach to developing, refining, evaluating, and implementing simulation interventions. The adapted framework guidance emphasizes: (1) identification of theory and existing evidence; (2) modeling and piloting interventions to clarify active ingredients and identify mechanisms linking the context, intervention, and outcomes; and (3) evaluation of intervention processes and outcomes in both the laboratory and real-world setting. The proposed framework will aid simulation researchers in developing more robust interventions that optimize simulation-based education and advance our understanding of simulation pedagogy.