The bactericidal effect of ultrasound was discovered over 90 years ago. Numerous studies have been carried out since then to use the technology for inactivation of pathogenic microorganisms in different food systems. With the development of ultrasound hardware in recent years and its wide application in the medical industry, time becomes ripe for the applications of ultrasound in the food safety arena. This chapter summarizes the theory and progress of power ultrasound (20 kHz to 100 kHz) in the past decade specifically on the application of inactivation of pathogenic microorganisms in liquids and on food surfaces. Efforts have been made to present a concise summary of the fundamental engineering aspects of power ultrasound and apparatus used in research. Recent studies on the inactivation of pathogens in liquid food systems and on fresh produce surfaces were presented. High intensity and short time (HIST) mano-thermo-sonication (MTS) treatment was highlighted as a promising method for liquid food pasteurization. For produce surface decontamination applications, several factors including uniformity of ultrasound field in the treatment chamber and the blockage of produce pieces to the propagation of ultrasonic waves were also emphasized.