Cancer of unknown primary (CUP) makes up a small percentage of newly diagnosed malignancies and is generally associated with a poor prognosis. Systematic evaluation of patients and close communication with pathology can often identify a suspected tissue of origin. It is critical to distinguish favorable prognosis subtypes of CUP from those with poor prognosis as favorable subtypes often have more effective treatment algorithms that can include curative intent treatment. For those with poor prognosis or no tentative tissue of origin identified, empiric chemotherapy is recommended using a taxane, platinum, or both. All cases require the attention of a multidisciplinary case conference and expert pathology review.