The addition of intraoperative radiotherapy (IORT) to the multimodality approach for the treatment of locally advanced and locally recurrent colorectal cancer seems to result in improvements in local control and long-term survival. Local control and survival are most likely in patients in whom a gross total resection is accomplished. Peripheral nerve is the dose-limiting structure for patients treated with IORT. Further improvements in local control require the addition of dose modifiers during external beam radiotherapy or IORT. Distant relapse remains problematic, and effective systemic therapy is necessary to significantly improve long-term survival.