Carcinoma of unknown histogenesis or primary site is an increasingly recognized syndrome regarded by most physicians as having a grim prognosis. Elaborate evaluations using low yield, and often misleading, radiologic studies focused on identifying primary sites in the lung, liver, pancreas, or gastrointestinal tract offer little benefit to the vast majority of patients. Increasing evidence has accumulated showing that subsets of patients within this broad syndrome exist in whom recognition and proper therapy may result in meaningful prolongation of life or potential cure. In this review, clinical clues and diagnostic aids for identification of nine treatable subsets of patients with the carcinoma of unknown origin (CUO) syndrome are emphasized. Current state-of-the-art treatment for each subset with subsequent end results are stated.