During 1996, an impressive number of new antineoplastic agents were approved by the United States Food and Drug Administration. In addition, advances in molecular biology are providing information about new targets against which to develop new agents. In this discussion, we will review some exciting new agents with previously documented antitumor activity that are excellent candidates for combining with radiation therapy. These agents include LY231514, a thymidylate synthase inhibitor that also interacts with dihydrofolate reductase and inhibits glycinamide ribonucleotide transformylase, a key enzyme in the de novo purine pathway. This drug has been evaluated in phase I studies and may possess radiosensitizing activity. Capecitabine is a 5-fluorouracil prodrug that is activated primarily in tumor tissue and is orally active. ONYX-015 is an attenuated adenovirus that only replicates in cells that have a p53-genetic mutation. Telomerase inhibitors also may be effective in preventing tumor recurrence following definitive radiation therapy. Several other agents are on the horizon and show promise as radiation sensitizers, though clinical data on the combinations are not yet available.