Water scarcity, expected to become more widespread in the coming years, demands renewed attention to freshwater protection and management. Critical to this effort are the minimization of freshwater withdrawals and elimination of wastewater discharge, both of which can be achieved via zero liquid discharge (ZLD), an aggressive wastewater management approach. Because of the high energetic cost of thermal desalination, ZLD is particularly challenging for high-salinity wastewaters. In this review, we discuss the potential of high-pressure reverse osmosis (HPRO) (i.e., reverse osmosis operated at a hydraulic pressure greater than ∼100 bar) to efficiently desalinate hypersaline brines. We first discuss the inherent energy efficiency of membrane processes compared to that of conventional thermal processes for brine desalination. We then highlight the opportunity of HPRO to reduce energy requirements for desalination of key high-salinity industrial wastewaters. The current state of membrane materials and processes for hypersaline brine desalination is also discussed, emphasizing several process design considerations unique to HPRO. Lastly, we discuss the most pressing research needs for the development of HPRO, notably the development of membranes and modules suitable for high pressures as well as fundamental studies of compaction and transport under HPRO conditions.