Metastasis of unknown primary origin (MUPO) account for 2–3 % of all malignancies in Western countries and represent a heterogeneous, often aggressive, and clinically challenging group of tumors with early metastatic dissemination for which a standardized diagnostic workup initially fails to identify the site of origin at the time of diagnosis. In the following chapter, we review the possibilities and challenges of tissue-based conventional as well as immunohistochimical procedures to categorize this heterogeneous group of neoplasms. We describe the role of pathology in MUPO diagnosis as part of a multidisciplinary effort primarily involving oncologists, surgeons, radiologists, and pathologists with the ultimate goal to aid in clinical reasoning and decision making.