Metastasis of unknown origin (MUO) constitutes between 5% and 10% of all noncutaneous cancers. An MUO is defined as a metastatic tumor for which the site of origin is not suggested by thorough history, physical examination, chest x-ray studies, routine blood and urine studies, and histologic evaluation. Two major groups of MUO can be defined: MUO to lymph nodes only (N1-3), and MUO to visceral sites. The prognosis may be quite good for patients with MUO limited to lymph nodes in the mid to high cervical, axillary, and groin areas. However, MUO in other lymph node areas is far more serious, with the possible exception of that in patients with a new syndrome, i.e., "advanced poorly differentiated carcinoma of unknown primary origin." There is some suggestion that these patients may respond to cisplatin-based combination chemotherapy. Patients with MUO to visceral sites have a poor prognosis. However, metastases from some primary tumors are sensitive to chemotherapy and a limited search for these tumors should be undertaken. These tumors include leukemia-lymphoma, germ cell tumors, small cell carcinoma of the lung, adenocarcinomas of the breast, ovary, endometrium, thyroid, or prostate, and possibly adrenal carcinoma. We start by reviewing the biochemical events of metastasis that may be targets for therapy. The importance of a correct tissue diagnosis is then considered, including the role of standard histochemistry, electron microscopy, enzyme histochemistry, and immunohistochemistry. The relatively limited value of radiologic tests in localizing the primary site of origin of the tumor is emphasized, as well as the limited role of currently available biomarkers. We conclude by discussing the treatment of each of the subtypes of MUO.