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In contrast to quantitative approaches designed to generalize what works in education, the qualitative nature of case studies (CSs) allows researchers to explore local explanations of what works. We argue that, combined with mixed methods (MM), CSs advance the responsible application of research because insider knowledge calls attention to critical generalizability considerations. To exemplify this claim, we describe the role of CSs within a large-scale statewide longitudinal study of college-readiness systems among public high schools. Also, we discuss the challenges and advantages of case selection and analysis using MM strategies that integrate quantitative and qualitative data sources. This presentation is appropriate to researchers using advanced case-centered MM approaches to support policy development for application in complex real-world instances.