Non-denaturing pressures of around 2000 bar are effective for eliminating and refolding protein aggregates and may be applicable in various phases of protein manufacturing to decrease aggregate levels in products and improve process yields. Lower aggregate levels can result in reduced immunogenicity of proteins and enable the correct refolding of proteins that might not be recovered with traditional techniques. High pressure treatment can also be used to conduct selective PEGylation and protease cleavage reactions while minimizing protein aggregation. High pressure processes have been used in the food industry for over 50 years and large scale (300 L) systems are commercially available, enabling production of proteins on the kilogram scale. This review summarizes the utility of high pressure refolding to remove and refold protein aggregates, enhance therapeutic proteins, and facilitate manufacturing improvements at industrial scales.