This article describes an operational framework for implementing translational simulation in everyday practice. The framework, based on an input-process-output model, is developed from a critical review of the existing translational simulation literature and the collective experience of the authors’ affiliated translational simulation services. The article describes how translational simulation may be used to explore work environments and/or people in them, improve quality through targeted interventions focused on clinical performance/patient outcomes, and be used to design and test planned infrastructure or interventions. Representative case vignettes are used to show how the framework can be applied to real world healthcare problems, including clinical space testing, process development, and culture. Finally, future directions for translational simulation are discussed. As such, the article provides a road map for practitioners who seek to address health service outcomes using translational simulation.