Biorefineries are expected to take over the production of chemicals and biofuels in the coming decades, in parallel to the depletion of fossil resources. Considerable research efforts have been made to develop efficient (bio)catalytic systems for the production of bio-based solvents and novel products with improved ecological footprints and “smart” properties. Among other challenges, water consumption will be an important aspect to assess in the full sustainability of biorefineries, which are envisaged for large-scale operations. The already existing fresh water shortage in many regions of our overpopulated planet has brought more pressure and uncertainties to these aims. Thus, over the past years, a number of enzymatic, fermentative, and chemocatalytic applications using seawater as a reaction medium for large-scale biorefineries have been reported by several research groups, which emphasize the use of nonpotable water resources for coastal regions and for locally available biomass (e.g., algae). This article contextualizes in detail these seawater-based applications for biorefineries. Overall, the use of such nonpotable water resources is promising, provided that applied catalytic systems can lead to straightforwardly treatable waste(sea)water effluents. Opportunities at the interface between biology, chemistry, and chemical engineering are foreseeable for (holistic) innovation and further research.