Chemoradiation is a standard approach to advanced unresectable head and neck cancer, although the optimum combination regimen remains controversial. However, in the past few years, chemoradiation has been successfully extended from the treatment of unresectable disease to the postsurgical therapy of high-risk patients and its value as an organ preservation procedure is under evaluation. More recently, molecular-targeted therapies have emerged, which interfere with mechanisms of chemo- and radioresistance, and preliminary data are promising. Their use in the combined treatment of head and neck cancer will hopefully further improve the value of chemoradiation in the clinical setting.