Radiosensitization with antimetabolites has improved clinical outcome for patients with solid malignancies, especially cancers of the GI tract, cervix, and head and neck. Fluorouracil (FU) and hydroxyurea have been widely used clinically during the last four decades, and promising results have been observed more recently with gemcitabine. Although the antimetabolites all target DNA replication, they differ with respect to the mechanisms by which they produce radiosensitization. The antimetabolite radiosensitizers may inhibit thymidylate synthase (TS) or ribonucleotide reductase, and the nucleoside/nucleobase analogs can be incorporated into DNA. Radiosensitization can result from chemotherapy-induced increase in DNA double-strand breaks or inhibition of their repair. Studies of repair pathways involved in radiosensitization with antimetabolites implicate base excision repair with the TS inhibitors, homologous recombination with gemcitabine, and mismatch repair with FU and gemcitabine. Gemcitabine can also stimulate epidermal growth factor receptor (EGFR) phosphorylation; inhibiting this effect with EGFR inhibitors can potentiate cytotoxicity and radiosensitization. Additional work is necessary to determine more precisely the processes by which antimetabolites act as radiation sensitizers and to define the optimal sequencing of these agents with EGFR inhibitors to provide better guidance for clinical protocols combining these drugs with radiotherapy.