It has been recognized that patients with CUP represent a heterogeneous group of tumors. Managing patients with CUP requires a complete medical history, careful consideration of findings on physical exam, targeted radiologic studies and pathologic analysis of biopsy and/or surgical specimens. Within this heterogeneous group there exist at least four subsets of patients with CUP, that based on clinicopathologic features are treated with regimens which have demonstrated efficacy in tumors originating in the most likely primary site of that CUP; squamous carcinoma involving mid or high levels of cervical lymph nodes, women with isolated axillary adenopathy containing adenocarcinoma, women with a predominant presentation of peritoneal carcinomatosis and young men with extragonadal germ cell syndrome.