Growing evidence suggests that intracellular signal pathways play a significant role in radiation response. Promising results have been obtained in experimental studies assessing the combined use of specific inhibitors and radiotherapy. Based on these data, a number of clinical trials were started to enhance tumor responses and thus to decrease the rate of locoregional recurrences. Several prognostic factors on tumoral radiosensitivity have been identified including intracellular signal pathways. Nevertheless, these factors do not correlate with responses to targeted therapies. Concerning rectal cancer, promising results have recently been obtained with concurrent radiotherapy and a monoclonal antibody against VEGF (bevacizumab). Studies combining cetuximab (anti-HER1) and radiotherapy will start soon in this setting. Other specific inhibitors combined with radiotherapy are still in preclinical evaluation.