Cancers of unknown primary (CUP) origin account for 2-3 % of all malignancies in Germany and represent a heterogeneous, often aggressive and clinically challenging group of tumors with early metastatic dissemination for which a standardized diagnostic work-up initially fails to identify the primary site of origin at the time of diagnosis. This article reviews the options and challenges of tissue-based conventional as well as molecular diagnostic procedures to categorize this heterogeneous group of neoplasms. The role of pathology in the diagnostics of CUP syndrome is described as part of a multidisciplinary effort involving oncologists, surgeons and radiologists with the ultimate goal of assisting clinical reasoning and decision-making.