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Therapy for patients with unknown primary carcinoma is evolving and requires a detailed understanding of the various clinicopathologic subsets with more favorable prognoses. For the remainder, and most patients with unfavorable prognoses, data on current empiric chemotherapy with the newer drugs seems to show improved overall survival compared with older historical data, including comparisons with large retrospective series and prospective phase II trial results. Several recent clinical trials have recently documented long-term survival for a minority of patients. The survival of patients with several metastatic adenocarcinomas of known primary sites, including colon/rectum, lung, and pancreas, has been improved by the administration of chemotherapy alone or combined with biologic targeted drugs (bevacizumab, erlotinib). Approximately 60% of the patients with unknown primary adenocarcinoma have clinically occult primary sites of colon/rectum, lung, and pancreas. Many of these patients will also benefit from therapeutic regimens now proven to be useful for patients with these known primary sites. All available data make a convincing argument that progress is being made for the commonly seen patients with adenocarcinoma of unknown primary site, and is likely to continue as understanding of these and other neoplasms further evolves.