Cancer of unknown primary ranks in the top ten cancer presentations and has an extremely poor prognosis. Identification of the primary tumour and development of a tailored site-specific therapy could improve the survival of these patients. We examined the feasability of using DNA methylation profiles to determine the occult original cancer in cases of cancer of unknown primary. ; The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme by the ERC Proof-of-Concept Grant EPICUP, under grant agreement No 640696 (to ME); the Cellex Foundation (to ME); the Institute of Health Carlos III (ISCIII) under the Integrated Project of Excellence number PIE13/00022 (ONCOPROFILE); Cancer Research Australia APP1048193 and AP1082604 and Victorian Cancer Agency TRP13062 (to DB, LM, and RT); the Samuel Waxman Foundation (to JML); the Health and Science Deapartments of the Generalitat de Catalunya (to JML and ME); and Ferrer (to ME).