Since the first application of high hydrostatic pressure (HHP) for food preservation more than 100 years ago, a wealth of knowledge has been gained on molecular mechanisms underlying the HHP-mediated destruction of microorganisms. However, one observation made back then is still valid, i.e. that HHP alone is not sufficient for the complete inactivation of bacterial endospores. To achieve "commercial sterility" of low-acid foods, i.e. inactivation of spores capable of growing in a specific product under typical storage conditions, a combination of HHP with other hurdles is required (most effectively with heat (HPT)). Although HPT processes are not yet industrially applied, continuous technical progress and increasing consumer demand for minimally processed, additive-free food with long shelf life, makes HPT sterilization a promising alternative to thermal processing.In recent years, considerable progress has been made in understanding the response of spores of the model organism B. subtilis to HPT treatments and detailed insights into some basic mechanisms in Clostridium species shed new light on differences in the HPT-mediated inactivation of Bacillus and Clostridium spores. In this chapter, current knowledge on sporulation and germination processes, which presents the basis for understanding development and loss of the extreme resistance properties of spores, is summarized highlighting commonalities and differences between Bacillus and Clostridium species. In this context, the effect of HPT treatments on spores, inactivation mechanism and kinetics, the role of population heterogeneity, and influence factors on the results of inactivation studies are discussed.