The enormous potential of harvesting energy from salinity gradients has been discussed for decades, and pressure-retarded osmosis (PRO) is being increasingly investigated as a method to extract this energy. Despite advancements in membranes and system components, questions still remain regarding the overall viability of the PRO process. Here, we review PRO focusing on the net energy extractable and the ultimate feasibility of the most widely explored configurations. We define the maximum energy that can be obtained from the process, quantify losses and energetic costs that will reduce the net extractable energy, and explain how membrane modules can be improved. We then explore the potential of three configurations of PRO: systems designed to control mixing where rivers meet the sea, power plants that utilize the high concentration gradients available from hypersaline solutions, and PRO systems incorporated into reverse osmosis desalination plants to reduce electricity requirements. We conclude by considering the overall outlook of the process and identifying the most pressing challenges for future research.