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High hydrostatic pressure (HHP) processing as a novel non-thermal method has shown great potential in producing microbiologically safer products while maintaining the natural characteristics of the food items. Scientific research of the process and its industrial applications has been widespread in the past two decades with many scientific publications describing its uses, advantages and limitations. The review describes the effect of HHP on foodborne pathogenic microorganisms, their structures and adaptive mechanisms, the intrinsic and extrinsic factors that affect its application with a focus on microbiological safety, and research needs. In a risk assessment context, tools and mechanisms in place to monitorize, optimize and validate the process, and procedures for assessing and modelling the lethal effect of the treatment are reviewed.