Carcinomas of unknown primary site are microscopically confirmed metastatic epithelial malignancies with no identified primary site at the onset of treatment. Their incidence is about 5% among all cancer patients. They represent a group of heterogeneous tumors with low chemosensitivity and poor outcome: the overall median survival is about 6 months. The search for primary tumor should be limited to the identification of subgroups of patients requiring specific therapies: 1) patients with cervical lymph nodes containing squamous carcinoma; 2) women with axillary lymph nodes containing adenocarcinoma; 3) women with peritoneal adenocarcinomatosis; 4) young men with poorly differentiated carcinoma of the midline; 5) patients with neuroendocrine metastasis. Other patients are to be managed with symptomatic procedures and possibly chemotherapy. Simple prognostic factors such as performance status, histology and serum levels of alkaline phosphatase may help the physician to select treatment strategies with the aim of preserving an optimal quality of life.