Cancer of unknown primary site (CUP) is defined as a metastatic disease, identified on biopsy, with it's origin remaining unknown despite extensive clinical, laboratory and imaging studies. As much as 3% to 10% of all cancers can be defined as CUP. The primary workup includes history taking, a full physical examination, basic laboratory studies, imaging studies and immunohistochemical staining or genetic analysis of biopsy material. The diagnostic yield of such studies is about 20% to 30% of cases. New advanced techniques can be used to define the genetic profile of the tumor cells. Comparing such profiles to those originating from known tumors may markedly improve our ability to detect the origin of CUP in up to 90% of cases. The treatment of CUP is based on the regimen given for cancer of the presumed origin, and in many cases is completely empiric. The prognosis for patients with CUP is dismal partially due to the late stages in which the disease is diagnosed and the aggressiveness of the tumor. The median survival is 10-12 months and the 2 year survival is 20%-25%. This is a case report demonstrating the dilemmas in managing such patients, followed by a review of the recent medical literature covering the topic.