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Leading cancer researchers update and review the mechanisms of action and the therapeutic selectivity and efficacy of 5-FU with and without leucovorin and its prodrugs in the treatment of colorectal cancer. Among the combination agents considered are UFT/LV, 5-FU/EU, capecitabine (Xeloda), S-1, and a variety of thymidylate synthase inhibitors. The authors discuss the potential advantages and disadvantages of these varied drugs and their mode of administration. Based on historical results with these agents when used alone, they also present a rationale for their results when used in combination with other agents.