Treatment of patients with cancer of unknown primary (CUP) syndrome according to the tissue of origin is part of the standard care if the suspected original tumor is similar in immunohistochemistry or in combination with clinical and laboratory parameters. Gene expression analysis or methylation assays can demonstrate similarities of the CUP samples with known tumors. A few retrospective analyses seem to show an advantage for patients who received a therapy that matched with the molecularly defined tumor. Currently, the superiority of such a therapy based on the molecularly defined tissue of origin is not proven. The search for molecular targets leads in a small proportion of patients to the possibility of targeted therapy with drugs approved for other indications and published case reports on such treatment.