Histotripsy is a novel therapeutic ultrasound technology that uses high-amplitude focused ultrasound pulses to mechanically liquefy tissue into subcellular debris. Unlike conventional high-intensity focused ultrasound (HIFU) thermal therapy, histotripsy offers several clinical advantages, including real-time monitoring using ultrasound imaging, reduced heat sink effects, effective tissue removal, tissue-selective capabilities, and immunostimulation. The technology is being evaluated in animal models for treating various conditions such as cancer, thrombosis, hematomas, abscesses, and biofilms, and has been approved by the US Food and Drug Administration (FDA) for liver tumor treatment. This review outlines the physical principles of histotripsy, its major parameters, hardware and software, imaging methods, and bioeffects, as well as its promising preclinical and clinical applications. Histotripsy can be categorized into cavitation histotripsy (CH) and boiling histotripsy (BH), with hybrid histotripsy (HH) being a recent development. CH uses microsecond-long pulses to generate cavitation clouds, while BH uses milliseconds-long pulses to produce boiling and mechanical fractionation. Both methods have been extensively explored in various organs and conditions. The review also discusses the instrumentation, image-guided targeting, and monitoring techniques for histotripsy, highlighting its potential in oncology, cardiac applications, blood clot treatment, and brain applications.Histotripsy is a novel therapeutic ultrasound technology that uses high-amplitude focused ultrasound pulses to mechanically liquefy tissue into subcellular debris. Unlike conventional high-intensity focused ultrasound (HIFU) thermal therapy, histotripsy offers several clinical advantages, including real-time monitoring using ultrasound imaging, reduced heat sink effects, effective tissue removal, tissue-selective capabilities, and immunostimulation. The technology is being evaluated in animal models for treating various conditions such as cancer, thrombosis, hematomas, abscesses, and biofilms, and has been approved by the US Food and Drug Administration (FDA) for liver tumor treatment. This review outlines the physical principles of histotripsy, its major parameters, hardware and software, imaging methods, and bioeffects, as well as its promising preclinical and clinical applications. Histotripsy can be categorized into cavitation histotripsy (CH) and boiling histotripsy (BH), with hybrid histotripsy (HH) being a recent development. CH uses microsecond-long pulses to generate cavitation clouds, while BH uses milliseconds-long pulses to produce boiling and mechanical fractionation. Both methods have been extensively explored in various organs and conditions. The review also discusses the instrumentation, image-guided targeting, and monitoring techniques for histotripsy, highlighting its potential in oncology, cardiac applications, blood clot treatment, and brain applications.