Colorectal cancer (CRC) is the second leading cause of cancer death in Western countries, and although the treatment of advanced CRC has progressed substantially, the improvements in response rates have not always been translated into a significant survival benefit. Until recently, the standard therapy for advanced CRC was a variety of biomodulated 5-fluorouracil (5-FU) regimens. 5-FU was used as first- or second-line therapy, and a different 5-FU regimen was used second line if first-line 5-FU therapy failed. Typically, the survival times for these patients were short and their quality of life poor. In recent years, a variety of new agents have emerged that have demonstrated activity in the treatment of advanced CRC. Of these, irinotecan (CPT-11) and oxaliplatin in combination with 5-FU and folinic acid (FA) have yielded the most promising results. However, only CPT-11 combined with either bolus or high-dose infusional 5-FU/FA, in randomized phase III studies, has demonstrated an increased response rate and median time to progression, producing a significant and clinically relevant survival advantage. In 2 randomized phase III studies, oxaliplatin/5-FU/FA demonstrated a clear increase in response rate over 5-FU/FA alone but failed to demonstrate a survival advantage. CPT-11 was approved by the Food and Drug Administration in April 2000 for the first-line treatment of advanced CRC in combination with 5-FU/FA.