Intraoperative radiation therapy (IORT) is an innovative treatment modality that has recently been given considerable attention as an approach toward controlling various locally advanced cancers. IORT involves surgical extirpation or debulking of the malignant lesion and the delivery of a large single dose of radiation to the tumor bed or to residual disease. This strategy allows for a theoretical enhancement of the therapeutic effect of radiation for three reasons: (1) the biologic effectiveness of a single large radiation dose is higher than for the same dose given in a fractionated regimen; (2) the dose of radiation is precisely given to the area at greatest risk of tumor recurrence (or persistence); and (3) irradiation of dose-limiting normal tissues may be avoided by operative mobilization of the tissues from the treatment volume by customized lead shielding of anatomically fixed structures or by judicious choice of electron beam energies or use of a bolus to limit dose to deep structures. Electrons are generally used for IORT because of sharp dose falloff. This avoids potential toxic effects to normal structures that may lie deep to the treatment volume. Conventional external beam photon radiation therapy (EBRT) allows less accurate tumor volume delineation (even with sophisticated treatment planning technique) and dose limitations necessitated by normal tissues incidentally in the treatment volume. A considerable amount of experimental and clinical data are available on the acute and late effects of IORT on normal tissues. Dose tolerances of many organs have been described in large animal models, and clinical toxicities are evident in several trials. Clinical IORT treatments are provided in more than 250 U.S. and foreign centers at the present time. Given the current interest in IORT, this monograph will review IORT methods and experimental and clinical results with emphasis on its present and future role for locally advanced cancers.