Radiotherapy continues to remain a major treatment modality for solid tumors. However, advances in fundamental radiobiology suggest that improvements in tumor control can be achieved through strategies that combine radiation and molecular targeting. One approach is to target a specific molecule involved in tumor cell survival after irradiation, which is currently being clinically evaluated using inhibitors of EGFR or Ras. Because of tumor heterogeneity and the existence of multiple tumor radio-resistance pathways, an extension of this approach being investigated at the pre-clinical level is to use Hsp90 inhibitors as a means of reducing the levels of multiple radioresponse regulatory proteins. In addition, it may also be possible to target normal tissue processes, such as angiogenesis, to enhance the radioresponse of tumors. Finally, an alternative approach to combining radiation and molecular targeting is to exploit radiation-induced gene expression to induce targets for other modalities or to increase their effectiveness.