5-Fluorouracil (5-FU) is one of the most potent antimetabolites which have been widely used in the treatment of advanced solid tumors. As an anticancer agent, because of its low efficacy and high toxicity, numerous modifications of 5-FU structure have been performed. A great number of novel 5-FU derivatives have been developed with highly efficient and much less toxic. In this paper, the recent development of novel 5-FU derivatives as potent antitumor agents is reviewed and discussed.