The pathologic work-up of patients with metestatic carcinoma of unknown primary can be a diagnostic challenge. Immunohistochemistry often plays a pivotal role in determining the cell lineage as well as the primary site of the malignancy. A variety of cells lineage, site specific associated antibodies and differential cytokeratins are now available as part of the armamentarium of the pathologist for the work-up of these cases. An algorithmic approach is recommended as well as the importance of interpreting the immunohistochemical results in the context of the clinical and other conventional morphologic parameters in order to establish a correct diagnosis to guide appropriate management and assess prognosis.