SummaryOne goal of the local-to-global research program is to explore ways to reduce, if not reverse, threats to sustainability through analysis using mathematical models applied to shared databases. This article describes a global case-study framework for reconciling top-down with bottom-up approaches so they are mutually reinforcing for identifying and evaluating the effectiveness of different scenarios describing potential future actions. A strategic selection of cases makes it possible to distinguish and represent concrete characteristics of both common and atypical situations, whereas a global model is needed to provide an integrating conceptual framework based on a theory of consumption, production, and international exchanges that captures interdependencies among activities across regions. I discuss how the results of global analyses can be useful for framing case-study questions and selecting cases, whereas the cases, in turn, identify concerns of specific stakeholders and provide detailed information, including technical data, to supplement economic databases with their accounting origins. I describe ways to enhance collaborations between top-down and bottom-up researchers, using global, multiregional input-output databases to play a mediating role, while avoiding rigidities of premature closure and incorporating diverse perspectives. Responding to the high-priority global challenge of vastly expanding effective sanitation services in developing countries is used to illustrate these ideas.