Abstract: Disclosed are 5?-substituted nucleoside monophosphates, which contain 5-fluorouracil or 5-fluorothiouracil as the nucleobase. In general, the 5?-substituted nucleoside monophosphates disclosed herein can inhibit human thymidylate synthase and thereby possess anti-cancer therapeutic effects. The 5?-substitution in these nucleoside monophosphates can prevent metabolic cleavage of the monophosphate group, mediated by enzymes such as 5?-nucleotidases, phospholipase D, etc. This feature can improve metabolic profiles, enhance target specificity, and/or reduce side effects of these compounds, compared to their corresponding unsubstituted analogs. Also disclosed are prodrugs of these 5?-substituted nucleoside monophosphates. After administration, the prodrugs can be metabolized to release their corresponding 5?-substituted nucleoside monophosphates. Methods of treating cancer using the 5?-substituted nucleoside monophosphates and prodrugs thereof are disclosed.