A multimodality regimen that includes EBRT, chemotherapy, maximal surgical resection, and IORT, when used in patients with initially unresectable primary colon or rectal adenocarcinoma, is associated with excellent long-term local control, and a 5-year overall survival of 52%. Distant metastases account for most treatment failures, occurring in roughly 50%. Treatment-related morbidity is high, with a long-term complication rate that approaches 50%. These results suggest that selected patients with advanced unresectable disease benefit from an aggressive approach. Additional effort needs to focus on reducing the rate of systemic failure with more effective chemotherapy regimens and minimizing the frequency of long-term procedural complications.