Despite more than 30 years of intensive studies on new drugs against advanced colorectal cancer, the fluoropyrimidines remain the drugs of choice for systemic treatment and for hepatic artery infusion (HAI). This overview describes new developments in advanced colorectal cancer chemotherapy, providing a rationale for more effective use of the fluoropyrimidines, with biochemical modulation, scheduling or by revealing biochemical mechanisms of action that correlate with antitumour activity. In human colorectal cancer cell lines and various animal tumour model systems 5-fluoro-2'-deoxyuridine (FdUrd) is more effective than 5-fluorouracil (5-FU). Comparably, FdUrd's modulation by leucovorin (LV) is more potent than 5-FU. In animal studies it is shown that intermittent high-bolus administration of FdUrd generates better antitumour activity, compared with equal toxic doses or any other schedule of 5-FU. These effects are related to prolonged-thymidylate synthase (TS) inhibition and the prevention of TS induction, rather than RNA incorporation. Preclinical studies with modulators such as N-phosphonacetyl-L-aspartate (PALA), WR-2721, mitomycin C and platinum derivatives provide a rationale for clinical use in the future. The first choice systemic chemotherapy of patients with advanced colorectal cancer remains 5-FU combined with LV. Some improvement in therapeutic efficacy has been achieved with locoregional HAI. In randomised studies HAI FdUrd improves the quality of life and survival as compared with optimal systemic therapy. Chronomodulation decreases toxicity, allowing dose intensification, while modulators such as LV or dexamethasone increase survival of patients treated with HAI FdUrd to 86% after 1 year. In conclusion, the clinical use of FdUrd has not been fully explored. Intermittent high-dose FdUrd, chronomodulation together with the use of modulators or drugs focused on prolonged TS inhibition, should be studied in large randomised studies.