The management of patients with unknown primary carcinoma (UPC) has evolved over the last few years and the recently developed sophisticated diagnostic modalities and novel therapies present both an opportunity for and a challenge to treatment of patients with this heterogeneous group of neoplasms. Recognition of patients with favorable prognostic factors is critical as specific therapies benefit these patients. Current empiric chemotherapy can offer a minority of patients with unfavorable prognostic factors substantial clinical benefit and improved survival. A focused search for the primary cancer is recommended in most patients. With the emergence of robust immunohistochemical stains and the growing field of molecular profiling, there is an increasing need for validation of a tailored approach to therapy. Our current focus is to study the impact of genetic profiling studies on patient outcomes and understand the limitations of currently available diagnostic studies. Although there are barriers to progress including tumor heterogeneity, challenging study designs, concerns with patient sample size, and inadequate research support, it is now important that an approach tailored to unknown primary subsets defined by the combination of clinical features, immunohistochemical stains, and molecular profiling be rigorously evaluated.