Carcinoma of unknown primary (CUP) is estimated to be 2% of diagnosed cancers. In the era of precision medicine, we are able to use more tools to identify a possible source of primary, direct potential treatments as well as provide prognostic information by use of molecular characteristics of the tumor. Here we provide a case of a 62-year-old woman with a remote stage I left sided colon adenocarcinoma s/p hemicolectomy who presented predominantly with a lung mass. Immunohistochemistry of the diagnostic tissue was suggestive of a primary but with the help of molecular profiling, more information was obtained and patient is being currently treated with a durable response. With our case as an example, we review some of the literature on additional molecular tests available to better define CUP and suggest some changes to European Society for Medical Oncology (ESMO) algorithm for evaluation of CUP.