New combinations of chemotherapy with radiotherapy for gastrointestinal cancers are showing evidence that improved outcomes may result from toxicity profiles associated with "targeted" systemic radiosensitizing agents. These new agents are also clinically attractive owing to such factors as oral bioavailability and patient dosing schedules, making them practical and convenient compared with older intravenous administration requirements. Several new classes of radiosensitizing agents are discussed here and underscore aspects of molecular activation in tumors rather than normal tissues because of differences in pathways of metabolism or based on the process of tumor-associated angiogenesis.