The environmental fragility of cities under advanced urbanization has motivated extensive efforts to promote the sustainability of urban ecosystems and physical infrastructures. Less attention has been devoted to neighborhood inequalities and fissures in the civic infrastructure that potentially challenge social sustainability and the capacity of cities to collectively address environmental challenges. This article draws on a program of research in three American cities—Boston, Chicago, and Los Angeles—to develop hypotheses and methodological strategies for assessing how the multidimensional and multilevel inequalities that characterize contemporary cities bear on sustainability. In addition to standard concerns with relative inequality in income, the article reviews evidence on compounded deprivation, racial cleavages, civic engagement, institutional cynicism, and segregated patterns of urban mobility and organizational ties that differentially connect neighborhood resources. Harnessing “ecometric” measurement tools and emerging sources of urban data with a theoretically guided framework on neighborhood inequality can enhance the pursuit of sustainable cities, both in the United States and globally.