NUT midline carcinoma (NMC) is a rare but under-diagnosed form of undifferentiated epithelial tumour. NMCs typically arise in the midline of the body and are characterized by a t(15;19) chromosomal translocation causing a fusion of the genes BRD4 and NUT. With an average survival time of only 9 months NMC is an extremely aggressive disease, affecting people of all ages. Increased awareness and the development of an immunohistochemical test have resulted in a steady rise of patients diagnosed with NMC. The lack of curative treatment makes the search for efficacious therapies imperative. Using a panel of three different NMC cell lines generated in our laboratory, we have started to systematically test conventional and novel therapeutic agents for this disease. Our data indicate that of the existing therapeutic approaches used in NMC, microtubule inhibitors and anthracyclines may be particularly effective drug classes. In addition, the CDK9 inhibitor flavopiridol demonstrated nanomolar efficacy in vitro and was more cytotoxic than several drugs previously used to treat NMC patients. In a mouse xenograft model of NMC, flavopiridol treatment significantly slowed tumor growth and doubled survival times without adverse toxicity. Notably, BRD4, the gene most commonly translocated to NUT in NMC, is one of several proteins that operate in a complex with CDK9 to regulate transcriptional activity within the cell. Since altered transcription is a feature of NMC, further investigation of the interaction between CDK9 and the BRD4-NUT fusion protein is essential to understand the mechanisms underpinning NMC. This study represents the first systematic evaluation of drug treatments for NMC, an essential first step to identify the optimal therapy approaches for this currently fatal cancer.