Abstract: Metastasis of unknown primary origin occurs in approximately 2% to 10% of all noncutaneous malignancies and makes up approximately 10% of new referrals to the hospital-based oncology centers. Determination of the primary site is based on histologic and cytologic examination, ancillary studies such as immunohistochemistry, and clinicopathologic parameters. However, occasionally a primary site is still not able to be determined, and therefore molecular studies are now being used to fill this void, using gene expression profiling. Although most of the molecular reports have reported good results, there are some limitations to this analysis, which is discussed. More recently, it has been suggested that identification of primary sites by molecular studies will be eventually replaced by using next-generation sequencing to determine the specific molecular signature to lead to mutation-specific rather than pathology-specific treatment.