Urbanization, population growth, and the accelerating consumption of food, energy, and water (FEW) resources bring unprecedented challenges for economic, environmental, and social (EES) sustainability. It is imperative to understand the potential impacts of FEW systems on the realization of the United Nation's Sustainable Development Goals (SDGs) as the world transitions from natural ecosystems to managed ecosystems at an accelerating rate. A major obstacle is the complexity and emergent behavior of FEW systems and associated networks, for which no single discipline can generate a holistic understanding or meaningful projections. We propose a research enterprise framework for promoting transdisciplinarity and top-down quantification of the interrelationships between FEW and EES systems. Relevant enterprise efforts would emphasize increasing FEW resource accessibility by improving coordinated interplays across sectors and scales, expanding and diversifying supply-chain networks, and innovating technologies for efficient resource utilization. This framework can guide the development of strategic solutions for diminishing the competition among FEW-consuming sectors in a region or country, and for minimizing existing inequalities in FEW availability when a sustainable development agenda is implemented.