Carcinoma of unknown primary origin (CUP) is a heterogeneous group of cancers defined by the presence of metastatic disease with no identified primary tumor at presentation. Identifying patients with prognostically favorable disease is important, since they may derive substantial benefit, including prolonged survival, from directed treatment. In CUP cases, a focused search for the primary tumor is recommended. Whether CUP is a distinct molecular genotype-phenotype relative to metastases of known cancers is unknown. However, use of a robust immunohistochemical panel and emerging molecular data may permit development of a tailored treatment algorithm for CUP patients that will include appropriate use of targeted agents.