The clinical presentation of cancer is heterogeneous with respect to biology, pathologic features, and responsiveness to cytotoxic treatment. Although some malignancies may be diagnosed early in their course, others present at an advanced stage with tumor metastases as the first sign of a malignant process. When tumors present at an advanced stage, taking a history, performing a physical examination, and conducting a directed diagnostic workup might identify the primary tumor site. But, in other instances, the source of the metastatic tumor cannot be identified despite this directed search. In this scenario, a diagnosis of metastatic cancer of unknown primary should be entertained. The definition of metastatic cancer of unknown primary is a biopsy-confirmed malignancy for which the site of origin is not identified by routine workup. This workup includes a complete history and physical examination. Additionally, this workup includes routine laboratory studies, chest x-ray, digital rectal examination with test for stool occult blood, and standard pathologic evaluation of the specimen. Women should undergo breast and pelvic examination, and men should have a complete prostate and testicular examination. The diagnosis of metastases of unknown primary site makes up 5% to 10% of all cancer patients, making it the seventh most common malignancy. The primary lesion, which has escaped detection by a staging workup, can be identified in only 30% to 82% of cases at autopsy. This inability to detect the primary tumor has two possible explanations. The first hypothesis is that the primary has involuted and is not detectable when the metastasis becomes evident. Although this is not a common phenomenon, spontaneous tumor regression has been described in several tumors. The second explanation is that the primary tumor’s malignant phenotype and genotype favor metastatic ability over local tumor growth. In this scenario, a slow-growing primary tumor might produce early metastatic lesions whose growth outstrips that of the parent tumor. This scenario of an unknown primary can be very unsettling to both the patient and the treating physician. The anxiety provoked by this clinical scenario may be caused by the uncertainty over treatment and an assumption of a grim prognosis, because current cancer treatment has been based on the identification of the primary tumor, but this disease entity actually represents a group of diseases with potentially widely divergent prognoses. When grouped together, patients with metastases from an unknown primary site have a median survival of approximately 6 months, despite therapy, but it is important to recognize that there are certain patient subgroups that have more responsive tumors and better prognoses. It is essential to conduct a consistent and thorough diagnostic evaluation to determine if a patient falls into one of these favorable subgroups, although one should avoid the use of needless, invasive tests. This approach enables the physician to optimize the treatment regimen for each patient. We describe the appropriate diagnostic workup of patients with metastases from an unknown primary site with emphasis on identification of patients with a favorable prognosis, and we highlight the treatment options available. Cases of metastases from an unknown primary usually fall into two possible categories: metastatic involvement to lymph nodes only, and those with visceral involvement. The most common sites for involvement of metastatic disease are to the lymph nodes, lung, bone, or liver. This is an important distinction because the patients with isolated nodal metastasis have a better prognosis with appropriate therapy.