The treatment of advanced colorectal cancer has been evaluated in a series of randomized trials, including infusional and modulated 5-fluorouracil (5-FU), and three meta-analyses encompassing trials of 5-FU plus leucovorin, continuous-infusion 5-FU, and intra-arterial fluoropyrimidines. A Southwest Oncology Group seven-arm phase II trial suggested that infusional 5-FU produced the most favorable toxicity spectrum and the longest survival, warranting further investigation in phase III trials. In a randomized phase III five-arm trial conducted by the Eastern Cooperative Oncology Group and the Cancer and Leukemia Group B, significant toxicity differences noted among the arms favored high-dose infusional 5-FU. In addition, the trial showed that 5-FU modulated by leucovorin or interferon was not more effective than 5-FU given as a 24-hour high-dose infusion weekly, and N-(phosphonacetyl)-L-aspartic acid did not enhance the activity of the weekly infusional 5-FU. Oral leucovorin provided no advantage over IV dosing. There was a significant difference in survival for patients with nonmeasurable disease (16.9 months) compared to those with measurable disease (12.6 months, P = .001). The Advanced Colorectal Cancer Meta-analysis Project demonstrated a response advantage for patients receiving 5-FU plus leucovorin (23%) compared to those receiving bolus 5-FU (11%, P = 10(-7); however, there was no survival advantage of 5-FU plus leucovorin over 5-FU alone (P = 0.57). The Meta-Analysis Group in Cancer showed that continuous-infusion 5-FU resulted in a statistically significantly higher response rate than bolus 5-FU (22% vs 14%, P = .0002). Overall survival also favored continuous-infusion 5-FU (P = .04). Continuous-infusion 5-FU was less toxic than bolus treatment. Data from six select randomized trials comparing hepatic intra-arterial infusion of FUDR to systemic therapy demonstrated a significant difference favoring intra-arterial therapy. Future directions for the treatment of advanced colorectal cancer include ongoing trials comparing low-dose vs high-dose infusional 5-FU, intra-arterial FUDR, leucovorin and dexamethasone vs systemic leucovorin plus 5-FU and proposed trials evaluating the dihydropyrimidine dehydrogenase inhibitor eniluracil plus oral 5-FU. Other drugs of interest include UFT, capecitabine, thymidylate synthase inhibitors, oxaliplatin, and irinotecan combinations.