Concerns over securing basic resources to an increasing world population have stressed the importance of critical interactions between the food, energy and water supply systems, as framed by the food-energy-water nexus concept. Current biorefineries producing first generation biofuels from food crops have impacted nexus resources, most notoriously land and food but also water and fossil energy resources required during cultivation and processing. Solutions to the nexus challenges of biorefineries require the search for alternative feedstocks and the application of methods that capture opportunities for synergistic interactions with the nexus. At the process level, more efficient water and energy use and food production could be possible if methods for extensive biomass fractionation, process integration and optimisation are developed. There is also a great opportunity to include the interactions between biomass supply and the nexus sectors in value chain optimisation to find strategic integrations that improve productivity and reduce losses and environmental impacts. By incorporating opportunities into a whole systems approach for design and planning, biorefineries will be able to balance nexus resource trade-offs, deliver their potential for full exploitation of biomass as the only source of renewable carbon and materials, and translate nexus issues into social welfare and sustainable development.