Cancer of unknown primary site (CUPS) is a heterogeneous entity defined by the presence of a histologically-proven metastatic neoplasm, in which the original tumor cannot be identified after a targeted study. The current guidelines for CUPS focus is not based on the search for the primary neoplasm but rather on the identification of patients who may benefit from a treatment that will prolong their survival, based on the clinical and histological characteristics of each case. By improving the diagnostic study, we avoid using fruitless tests in patients with limited therapeutic possibilities and poor short-term prognosis.