Eighty-five percent of United States citizens live in urban areas. However, research surrounding the resilience and sustainability of complex urban systems focuses largely on coastal megacities (>1 million people). Midsize cities differ from their larger counterparts due to tight urban-rural feedbacks with their immediate natural environments that result from heavy reliance and close management of local ecosystem services. They also may be less path-dependent than larger cities due to shorter average connection length among system components, contributing to higher responsiveness among social, infrastructural, and ecological feedbacks. These distinct midsize city features call for a framework that organizes information and concepts concerning the sustainability of midsize cities specifically. We argue that an integrative approach is necessary to capture properties emergent from the complex interactions of the social, infrastructural, and ecological subsystems that comprise a city system. We suggest approaches to estimate the relative resilience of midsize cities, and include an example assessment to illustrate one such estimation approach. Resilience assessments of a midsize city can be used to examine why some cities end up on sustainable paths while others diverge to unsustainable paths, and which feedbacks may be partially responsible. They also provide insight into how city planners and decision makers can use information about the resilience of midsize cities undergoing growth or shrinkage relative to their larger and smaller counterparts, to transform them into long-term, sustainable social-ecological systems.