As the global population grows, consumption of water, energy, and food will also increase, placing stresses on these three sectors, raising the importance of the Water-Energy-Food Nexus (WEFN). This article highlights research challenges and identifies process systems engineering research opportunities to appropriately model and optimize the WEFN. A brief overview of relevant, foundational WEFN research is first presented. We then identify challenges in the multiple scales of the WEFN, ranging from the household scale to the global scale. There are further challenges with appropriate system boundary definitions, and challenges in modeling the decision-making and conflicting objectives of multiple stakeholders in the WEFN. Uncertainties of all kinds appear at all scales of the WEFN and must also be considered. We use two motivating WEFN examples to frame these challenges and propose future avenues and opportunities for research. Possible approaches to the abovementioned challenges are proposed. (C) 2016 Elsevier Ltd. All rights reserved.