Many a dose and schedule of single agent of 5-fluorouracil (5-FU) has been evaluated to improve therapeutic outcome for four decades. No standard or an optimal dose and schedule has been established yet despite intensive clinical, investigation. Since 5-FU seems to have dual, mechanisms of cell kill; DNA and RNA directed cytotoxicity, it is important to know how to maximize or improve therapeutic ratio by dosing or scheduling 5-FU administration, even modulating 5-FU with other agents. Currently, protracted infusion (PI) appears to be a sort of optimal administrative method of 5-FU considering both tumor response and side effects, more convenient new oral 5-FU derivatives, of which pharmacological profiles are similar to PI, will soon take over its role in 5-FU therapy.