Although significant advances have been made in the treatment of advanced/metastatic colorectal cancer, 5-fluorouracil (5-FU) still forms the basis of chemotherapy. Recently, new 5-FU schedules and novel fluoropyrimidines have been developed, but there are no trials directly comparing these regimens. The current review describes the mechanisms of action, pre-clinical and phase I/II studies of two oral fluoropyrimidine therapies, capecitabine and uracil with tegafur plus leucovorin. It also compares the phase III studies of these agents with those of the two most popular infusional 5-FU-based regimens: de Gramont and German AIO (The Association of Medical Oncology (AIO) of the German Cancer Society). Both oral and infusional regimens demonstrated similar survival to the Mayo Clinic regimen, a standard treatment for colorectal cancer. Therefore, other endpoints must be examined to decide optimum therapy, including response rates, time to disease progression, tolerability and patients' convenience. All four new therapies demonstrated superior safety profiles compared with the Mayo Clinic regimen. However the uracil with tegafur plus leucovorin regimen was associated with severe diarrhoea and capecitabine with hand -foot syndrome. Patients will not sacrifice efficacy for the convenience of oral therapy alone, therefore the fact that capecitabine achieved superior response rates and equivalent time to disease progression compared with the Mayo Clinic regimen, while uracil with tegafur plus leucovorin produced lower response rates and significantly inferior time to disease progression, is highly relevant in choosing treatment. British Journal of Cancer (2002) Colorectal cancer is the third most common cancer in men and women, accounting for 783 000 new cases and 437 000 deaths worldwide in 1990 Parkin et al, 1999). About 40 -50% of patients develop metastatic disease. The aims of any therapy in patients with advanced colorectal cancer are to control symptoms, maintain or improve quality of life and ultimately to prolong survival. Recent meta-analyses confirmed that chemotherapy prolongs time to disease progression (TTP) and survival in patients with advanced or metastatic colorectal cancer, compared with best supportive care or observation/no chemotherapy (Colorectal Cancer Collaborative Group, 2000;Jonker et al, 2000).The fluoropyrimidine, 5-fluorouracil (5-FU), has formed the basis of chemotherapy for colorectal cancer for over 40 years. Numerous 5-FU-based schedules are used, and extensive efforts have been made to increase their activity, including biomodulation, modification of the dose or schedule and the use of analogues/ prodrugs.The most successful biomodulation of 5-FU has been with leucovorin (LV), a derivative of tetrahydrofolic acid, the reduced form of folic acid. The rationale is that in the presence of reduced folate, fluorodeoxyuridine monophosphate (a metabolite of 5-FU), covalently interacts with thymidylate synthase, which is the source for de novo synthesis of thymidine nucleotides, ultimately di...