Within the past decade, there have been considerable advances in the first- and second-line treatment of colorectal cancer (CRC). For many years, 5-fluorouracil was the only therapeutic option for the first-line treatment of CRC, and virtually no effective salvage therapies were available. However, the advent of oxaliplatin and irinotecan has improved outcomes for advanced CRC, providing increased therapeutic choice in the first-line setting and effective salvage therapies. Many patients are now receiving multiple lines of therapy, and it is in the setting of previously treated CRC that cetuximab, a monoclonal antibody to the epidermal growth factor receptor, has been successfully developed based on sound scientific principles. The ability to integrate new biologic therapies with conventional cytotoxic agents marks a new treatment era for this disease. This review discusses the development of cetuximab in pretreated CRC to date and future directions with this novel therapy.