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Cytotoxic chemotherapy for colorectal cancer has undergone a period of dramatic development over the course of the last 5 years. Four distinct classes of drug with activity in this disease are now available, and the current challenge is to establish the best way to use these agents, either in sequence or in combination, for the benefit of patients. This review aims to summarize the data relating to the newer agents and to propose directions for future research. DRUGS TARGETING THYMIDYLATE SYNTHASE 5-fluorouracil (5-FU) has established single-agent activity in advanced colorectal cancer. Its main intracellular target is thymidylate synthase, which is inhibited by the active metabolite of 5-FU, 5-fluorodeoxyuridine monophosphate (FdUMP) (Figure 1). The lack of alternative agents until recent years has fuelled extensive research into the biochemical modulation of 5-FU and alternative methods of delivery, primarily based on continuous infusion of the drug. Many individual clinical trials have demonstrated enhanced response rates when 5-FU is co-administered with folinic acid (calcium leucovorin). However a significant survival benefit has been more difficult to establish. Indeed a meta-analysis of nine trials showed no survival advantage for folinic acidmodulated 5-FU over 5-FU alone (Advanced Colorectal Cancer Meta-Analysis Project, 1992). Similarly, continuous infusion of 5FU using a variety of different schedules also enhances response rates over bolus delivery. A meta-analysis of seven randomized trials addressing this question showed a small but statistically significant improvement in median survival for 5-FU infusion over 5-FU bolus (12.1 vs 11.3 months, P = 0.039). Haematological toxicity was also significantly less common with 5-FU infusion, underlining the improved therapeutic ratio provided by this approach (Meta-analysis Group In Cancer, 1998). Drawing on the experience gained with 5-FU infusion, two new avenues of drug development have been explored. The direct thymidylate synthase (TS) inhibitors are a group of rationally designed molecules that compete with folinic acid for binding to TS (Figure 1). Intracellular polyglutamation of some of these compounds leads to their retention within the cell, and hence prolonged inhibition of TS. Raltitrexed, the lead agent in this class, has been the subject of extensive clinical evaluation. Its efficacy at the established dose of 3 mg m −2