Abstract: Cancer of unknown primary (CUP) is histologically confirmed, metastatic malignancies with a primary tumor site that is unidentifiable on the basis of standard evaluation and imaging studies. Clinical detection, immunohistochemistry, gene expression profile, DNA methylation, next-generation sequencing, microRNA detection, and other methods were used to trace the origin of CUP. With the continuous development of tracing and localization technologies for CUP origin, more methods for locating the primary foci of CUP have been developed. These techniques will contribute to the clinical evaluation, diagnosis, and treatment of CUP, and improve the prognosis of patients. This article reviewed the research progress of tracing and locating methods of CUP, to provide a new method and theoretical basis for clinical treatment.