The diagnosis of carcinoma of unknown primary (CUP) is made after exclusion of the presence of a mucosal primary. There are two mains options for the primary treatment of CUP, either a neck node dissection followed by postoperative radiotherapy or chemo-radiotherapy, or a primary radiotherapy or chemo-radiotherapy depending on the nodal stage followed in case of residual neck disease by a selective neck dissection. There is no data to suggest the superiority of one over the other. For radiotherapy, unilateral neck or bilateral neck, including the upper aerodigestive tract mucosa are possible options. There is no definite data to demonstrate the superiority of one over the other, but owing the reduced toxicity of unilateral irradiation, and the possibility of salvage treatment in case of emergence of a mucosal primary and/or a contralateral neck node development, the former may be the preferred option. Advances in radiotherapy such as intensity modulated radiation therapy have the potential to spare organs at risk and reduce late toxicity rates. A selective irradiation approach customized on "major" criteria, such as nodal stage and level, HPV and EBV status and accessory criteria, such as histological variants, is under investigation.