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Cancer of unknown primary (CUP) is a metastatic syndrome with an unidentifiable primary tumor even after comprehensive clinical and pathological investigations, accounting for approximately 2%-5% of all newly diagnosed cancers. CUP has some common features including aggressiveness, early dissemination and poor prognosis. With the application of novel molecular tests and drugs, the diagnostic value of gene expression assay and genomic tests in characterizing the molecular features has become increasingly prominent, and new treatment options such as molecular-guided targeted therapy and immunotherapy have become available. This article reviewed the clinical trials of CUP reported at 2023 European Society for Medical Oncology (ESMO) Congress.