In 2011, the US Environmental Protection Agency’s (EPA) Office of Research and Development program, Sustainable and Healthy Communities, coined the term TRIO (Total Resources Impact Outcome) to represent approaches that fully incorporate all three pillars of community sustainability—environmental, economic and social. This holistic approach to sustainability is embodied in the Human Well-Being Index (HWBI) comprised of sub-indices representing environmental well-being, economic well-being and societal well-being (which includes basic human needs and subjective well-being). The development of the HWBI is described in this manuscript along with its application at national, state and county spatial scales. In addition, application at even smaller spatial scales (communities, neighborhoods, demographic and economic sub-groups, and even individuals) is discussed. The potential utility of HWBI for comparing the intended and unintended consequences of alternative decisions is described.