The role of oral chemotherapy has been getting expanded because of the potential advantage in patients convenience and better quality of life as well as in cost-effectiveness as compared with intravenous chemotherapy. In this article, the history, mechanism of anti-tumor activity, and clinical use of oral chemotherapy using 5-fluorouracil (5-FU) derivative chemotherapeutic agents are reviewed. Pharmacological analysis has revealed that 5-FU, a basic chemotherapeutic agent widely used against a variety of malignant tumors, shows a time dependent anti-tumor activity, and that continuous maintenance of 5-FU concentration in blood is the optimal method in 5-FU administration. UFT, a combination drug of ftorafur (tetrahydrofuranyl-5-fluorouracil, tegafur, FT) and uracil, has been developed to have potent anti-tumor activity by maintaining higher 5-FU concentration in blood and tumor tissues for a long time. FT is a pro-drug that releases 5-FU continuously, and uracil is added to inhibit degradation of the released 5-FU. Clinically, oral administration of UFT has proved to be effective as an adjuvant therapy after surgery for some malignant tumors such as non-small cell lung cancer. Moreover, UFT has proved to be effective for inoperable advanced malignancies such as colorectal cancer, especially in combination with leucovorin or cisplatin. Recently, S-1, a more active oral 5-FU derivative chemotherapeutic agent has been developed in Japan. Several factors to affect anti-tumor effects and/or toxicities of 5-FU and the derivatives, such as thymidylate synthase activity, dehydropyrimidine dehydrogenase activity and p53 status, are also discussed in the article. In conclusion, oral administration of 5-FU derivatives such as UFT may have several clinical advantages over intravenous 5-FU administration.