Simple Summary Four decades ago, intraoperative electron radiation therapy (IOeRT) was developed to improve precision in local cancer treatment by combining real-time surgical exploration and resection with high-energy electron irradiation. The technology of ultra-high dose rate electron and other radiation beams known as FLASH irradiation sharply increases its interests, as data from preclinical experiments have proven a marked favorable effect on the therapeutic index: similar cancer control with a clearly improved tolerance of many normal tissues to high doses of irradiation. The knowledge and tools regarding technology, physics, biology, and preclinical results in heterogeneous cancers opens great opportunities towards the path of developing the first clinical applications of the emerging FLASH technology via clinical trials based on state-of-the-art medical practice with IOeRT. Introduction: The clinical practice and outcome results of intraoperative electron radiation therapy (IOeRT) in cancer patients have been extensively reported over 4 decades. Electron beams can be delivered in the promising FLASH dose rate. Methods and Materials: Several cancer models were approached by two alternative radiobiological strategies to optimize local cancer control: boost versus exclusive IOeRT. Clinical outcomes are revisited via a bibliometric search performed for the elaboration of ESTRO/ACROP IORT guidelines. Results: In the period 1982 to 2020, a total of 19,148 patients were registered in 116 publications concerning soft tissue sarcomas (9% of patients), unresected and borderline-resected pancreatic cancer (22%), locally recurrent and locally advanced rectal cancer (22%), and breast cancer (45%). Clinical outcomes following IOeRT doses in the range of 10 to 25 Gy (with or without external beam fractionated radiation therapy) show a wide range of local control from 40 to 100% depending upon cancer site, histology, stage, and treatment intensity. Constraints for normal tissue tolerance are important to maintain tumor control combined with acceptable levels of side effects. Conclusions: IOeRT represents an evidence-based approach for several tumor types. A specific risk analysis for local recurrences supports the identification of cancer models that are candidates for FLASH studies.