Several modifications to the administration schedule of 5-fluorouracil (5-FU) alone or in combination with other agents have been investigated in advanced colorectal cancer. Biochemical modulation of 5-FU with leucovorin (LV) increases response rate compared with 5-FU alone, but without improvement of overall survival. The best treatment schedule and optimal dose of LV remain unclear, although low doses seem equally as effective as high doses, with the advantage of reduced cost. Methotrexate can increase the activity of 5-FU to a similar degree as LV and a recent meta-analysis showed a slight improvement in survival. The combination of 5-FU + interferon has been disappointing, with phase III trials showing similar activity to 5-FU + LV, but with high toxicity. Other modulators (e.g. hydroxyurea, N-phosphonacetyl-L-aspartate, dipyridamole) show promising but sometimes conflicting results. Standardisation of assessment criteria should be considered when comparing these data to the activity of new drugs such as 'Tomudex' (raltitrexed, previously known as ZD1694), CPT-11 and oxaliplatin.