In recent years the concept of metabolic modulation of fluoropyrimidines by leucovorin has been introduced clinically in patients with advanced colorectal cancer, breast cancer, gastric cancer and head and neck cancer among others. The concept of metabolic modulation was developed in the laboratory and employed clinically. Leucovorin is a noncytotoxic compound used to increase the therapeutic efficacy of 5-fluorouracil. Following 5-fluorouracil activation to 5-fluorodeoxyuridine monophosphates, its binding to thymidylate synthase is stabilized by the active cofactor, 5,10 methylene tetrahydrofolate and its polyglutamate forms. Under these conditions, both the extent and duration of inhibition of thymidylate synthase and consequently, DNA synthesis are more pronounced. The results of clinical trials (phase II and III) indicate that the response rates to 5-fluorouracil/leucovorin modulation are significantly higher than that of fluorouridine alone.