Cancer of unknown primary site (CUP) ranks as the fourth most common cause of cancer deaths and represents both a diagnostic and a management challenge. In CUP, the regression or dormancy of the primary tumor, the development of early, uncommon, systemic metastases, and the resistance to therapy are hallmarks of this heterogeneous clinical entity. Still, no consensus exists on whether CUP is simply a group of metastatic tumors with unidentified primaries or a distinct entity with specific genetic/phenotypic aberrations that define it as "primary metastatic disease." In this review, we present karyotypic analyses as well as the single-gene, single-protein studies done on the expression of oncogenes, tumor- or metastasis-suppressor genes, as well as angiogenesis effectors. These studies show frequent expression of oncoproteins, lack of activating epidermal growth factor receptor/c-Kit mutations or amplification, uncommon presence of tumor- or metastasis-suppressor gene mutations and highly active angiogenesis in CUP. Informative as they may be, these data have been observed in several solid tumors of known primary and failed to identify a CUP-specific molecular signature. The latter, if it exists, probably consists of a multigene expression pattern not captured by single-gene studies. Gene and protein microarray technologies offer promise for the unraveling of complex genetic programs that would either identify each CUP's primary tissue of origin or instead define the CUP-specific molecular signature. Confirmation of one of the two hypotheses would either improve primary disease-oriented therapy or develop CUP-oriented treatments targeting molecular aberrations that drive neoplastic growth/dissemination.