High-pressure processing (HPP) kills microorganisms effectively, resulting in foods of very good microbiological quality, with enhanced safety and longer shelf life. For inactivation of bacterial endospores, the most pressure-resistant organisms, simultaneous application of heat is usually required. High pressure is a valid technology for replacement of heat treatment of some food products. Combination of pressure treatment with other physical or chemical treatments, not only exploiting membrane damage but also having different targets in the microbial cells, is recommended to guarantee food safety and preservation because a fraction of the microbial population is often only sublethally injured by high pressure. The combined treatment, based on the hurdle concept, has a killing effect greater than that of pressurization alone, with the effect sometimes being synergistic.