In the last decade, research focus has shifted to testing rapidly emerging classes of agents that specifically target signaling pathways within tumor cells or microenvironment. Though their effects given as single agents are generally limited, many of these compounds have the capability to sensitize tumors to radiation or cytotoxic drugs. Actively investigated approaches include combining anti-EGFR agents, bioreductive hypoxic cell toxins, anti-angiogenesis agents, or inhibitors of multiple signaling pathways with radiotherapy. J. Surg. Oncol. 2008;97:708–711. © 2008 Wiley-Liss, Inc.