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NUT carcinoma (NC) is a rare, highly invasive and fatal tumor and often misdiagnosed. It typically arises from the mediastinum and midline organs and has complicated pathogenesis and poor outcome. Genetically, its pathogenesis is related to a chromosomal rearrangement involving the NUTM1 gene. In most cases, the main oncoprotein is BRD4-NUT with a translocation between NUTM1 and BRD4 genes, but in a few cases, the oncoprotein is BRD3-NUT , or NSD3-NUT . Studies have shown that the histone hyperacetylation and BRD4 hyperphosphorylation may lead to the activation of cancer circuits. Abnormal production of microRNA, inactivation of tumor suppressor genes and abnormal activation of several signaling pathways are proposed as potential mechanisms underlying the pathogenesis of NC. Currently, there is no consensus on its standard treatment for NC. Extent of surgical resection with negative margins, initial radiotherapy and part of chemotherapy regimens may significantly associated with the improvement of progression-free survival (PFS) rate and overall survival (OS) rate. Some bromodomain and extraterminal inhibitors (BETis) have shown encouraging results in the clinical trials on NC, but delayed drug resistance is still an important issue that needs to be resolved. Histone deacetylase inhibitors are also found to possess the potential in the treatment of NC. Herein, we summarize recent advances in the pathogenesis and treatment of NC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-1884). The authors have no conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)