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Background: The European Society of Medical Oncology (ESMO) recently published extensively revised guidelines on cancer of unknown primary (CUP). The new version contains the following relevant amendments: with respect to diagnostics of CUP, the current guidelines aim for a more precise and standardized definition of CUP by establishing diagnostic algorithms. Recommendations for molecular diagnostics of cancer tissue have also been implemented. With respect to CUP classification, the favorable category has been revised. A carcinoma with immunohistochemistry typical for renal cell carcinoma (renal-like CUP) was introduced in the new definition of favorable subtypes, for which a specific treatment is indicated. Based on a newly defined oligometastatic situation a subgroup with localized cancer potentially curatively treatable with surgery and/or radiotherapy was introduced into the CUP classification. With respect to treatment of CUP, the current guidelines present options beyond empirical chemotherapy, which is still the standard of care treatment, and pinpoint indications and predictive biomarkers for targeted and immune checkpoint inhibitor treatment., Relevant Updates: The European Society of Medical Oncology (ESMO) recently published extensively revised guidelines on the CUP syndrome. The new version contains the following relevant amendments: the current guidelines aim for a more precise and standardized definition of CUP by establishing diagnostic algorithms with respect to the diagnostics of CUP syndrome. Recommendations for molecular diagnostics of cancer tissue have also been implemented. The classification of the CUP syndrome has also been revised. A carcinoma with immunohistochemistry typical for renal cell carcinoma (renal-like CUP) was introduced in the new definition of favorable subtypes, for which a specific treatment is indicated. Based on a newly defined oligometastatic situation a local potentially curatively treatable with surgery and/or radiotherapy subgroup was introduced into the CUP classification. With respect to treatment of the CUP syndrome, the current guidelines present options beyond empirical chemotherapy, which is still the gold standard treatment, and pinpoint indications and predictive biomarkers for targeted and immune checkpoint inhibitor treatment., Schlussfolgerung: The aim of this review is to present the current state of diagnostics, classification and treatment of CUP syndrome, with a focus on recent developments and revisions implemented in the current ESMO guidelines., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)