Despite the general perception that chemotherapy for metastatic colorectal cancer is ineffective, over the past decade improvements have been reported. More than 30 years after its introduction into clinical trials, 5-fluorouracil (5-FU) remains the most active single agent in the treatment of metastatic colorectal carcinoma, even though response rates are usually less than 20%. In an effort to improve outcome, investigators have been attempting to exploit the efficacy of 5-FU in various ways. Recent innovations include attempts to biochemically modulate the activity of 5-FU with other drugs, delivering 5-FU by hepatic arterial infusion, and using administration schedules that consider the biology of this tumor and the pharmacokinetics of the drug. Small but clinically significant improvements in efficacy have resulted from these attempts. The results of clinical trials using these approaches and their current and potential future clinical significance are discussed.