Preoperative chemoradiotherapy and radiotherapy with an integrated boost offer excellent local control rates in patients with rectal cancer. The introduction of intensity-modulated radiotherapy and image-guided radiotherapy has drastically improved the tolerance of these treatments. The new challenge is developing organ-preserving strategies and curative treatments for medically inoperable patients. Contact radiotherapy seems efficient for small tumors. Tumor hypoxia limits the success of radiotherapy for locally advanced cancers. Modulation of the L-arginine/iNOS pathway and implementation of hypoxia imaging in radiotherapy planning may overcome this hurdle.