Although 5-fluorouracil (5-FU) has been used to treat advanced colorectal cancer for 45 years, the drug has only a modest response rate and impact on survival. Attempting to enhance 5-FU's activity, researchers have administered it in combination with biochemical modulators and changed its dosage schedules to increase dose intensity. The combination of 5-FU and leucovorin has been evaluated in many studies. Results of a meta-analysis comparing 5-FU administered by bolus injection with a combination of 5-FU and intravenous leucovorin indicate that the combination significantly increased response rates but failed to improve survival. Similarly, studies comparing different methods of 5-FU administration (bolus injection v prolonged infusion) have demonstrated improved response rates and decreased toxicity with prolonged infusion, but most have failed to demonstrate statistically significant improvements in survival. For patients with liver-dominant colorectal disease, researchers have investigated the administration of liver-directed therapy by techniques such as hepatic arterial infusion (HAI). Compared with systemic administration of fluoropyrimidines, HAI administration increased response rates, but no survival benefit was demonstrated. Both response and survival benefits were observed with HAI, however, in one trial comparing HAI with no treatment (palliative care) in previously untreated patients with liver metastases. This trial also demonstrated that HAI did not diminish quality of life. Intravenous fluoropyrimidine-based therapies continue to dominate as the first-line approach for patients with advanced colorectal cancer. Present and future clinical trials will determine the efficacy of 5-FU pro-drugs, regimens combining oral 5-FU and 5-ethynyluracil, thymidylate synthase inhibitors, and new 5-FU combination regimens (5-FU plus oxaliplatin [Eloxatine; Sanofi, New York, NY] or irinotecan [CPT-II, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI], for example).