Histotripsy is a novel ultrasound-based therapy that mechanically liquefies tissue into subcellular debris using high-amplitude focused ultrasound pulses. Unlike conventional high-intensity focused ultrasound (HIFU) thermal therapy, histotripsy offers real-time monitoring via ultrasound imaging, sharp lesion margins, effective tissue removal, tissue selectivity, and immunostimulation. It is being evaluated in preclinical and clinical studies for treating cancer, thrombosis, hematomas, abscesses, and enhancing immune responses. Histotripsy has been approved by the FDA for liver tumor treatment and is used for benign prostatic hyperplasia and renal tumors. The technology relies on bubble activity generated by ultrasound pulses, which mechanically disrupt tissue without thermal damage. Two main approaches—cavitational histotripsy (CH) and boiling histotripsy (BH)—are used, with CH relying on microbubbles and BH on vapor bubbles. Hybrid histotripsy (HH) combines both methods. Histotripsy has tissue-selective advantages, preserving critical structures while liquefying tumors. It is effective for various applications, including cancer, cardiac diseases, thrombosis, and neurological conditions. The technology uses specialized hardware and software, with imaging methods for real-time monitoring. Histotripsy-induced lesions are reabsorbed by the body, leaving minimal scar tissue. Preclinical and clinical studies show its potential in treating a wide range of diseases, including liver tumors, brain tumors, and blood clots. Histotripsy also shows promise in immunotherapy by inducing antitumor immune responses. The technology is being developed for various applications, including transcranial brain treatment, where it can safely ablate tumors without thermal damage. Histotripsy is a rapidly growing field with significant clinical and research potential.Histotripsy is a novel ultrasound-based therapy that mechanically liquefies tissue into subcellular debris using high-amplitude focused ultrasound pulses. Unlike conventional high-intensity focused ultrasound (HIFU) thermal therapy, histotripsy offers real-time monitoring via ultrasound imaging, sharp lesion margins, effective tissue removal, tissue selectivity, and immunostimulation. It is being evaluated in preclinical and clinical studies for treating cancer, thrombosis, hematomas, abscesses, and enhancing immune responses. Histotripsy has been approved by the FDA for liver tumor treatment and is used for benign prostatic hyperplasia and renal tumors. The technology relies on bubble activity generated by ultrasound pulses, which mechanically disrupt tissue without thermal damage. Two main approaches—cavitational histotripsy (CH) and boiling histotripsy (BH)—are used, with CH relying on microbubbles and BH on vapor bubbles. Hybrid histotripsy (HH) combines both methods. Histotripsy has tissue-selective advantages, preserving critical structures while liquefying tumors. It is effective for various applications, including cancer, cardiac diseases, thrombosis, and neurological conditions. The technology uses specialized hardware and software, with imaging methods for real-time monitoring. Histotripsy-induced lesions are reabsorbed by the body, leaving minimal scar tissue. Preclinical and clinical studies show its potential in treating a wide range of diseases, including liver tumors, brain tumors, and blood clots. Histotripsy also shows promise in immunotherapy by inducing antitumor immune responses. The technology is being developed for various applications, including transcranial brain treatment, where it can safely ablate tumors without thermal damage. Histotripsy is a rapidly growing field with significant clinical and research potential.