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Abstract Background Natural products from herbal medicines have long been investigated for their potentials as cancer therapeutics. Besides the development of several herbal medicine-derived anti-cancer agents, such as paclitaxel, vincristine and podophyllotoxin, many recent laboratory findings demonstrated that brusatol, a quassinoid from the seeds of Brucea sumatrana, exhibits potent tumor suppressing effect with improved disease outcome. Our recent finding further demonstrated that brusatol synergizes with the intrinsic metabolic burden in cancer cells. Main body Here, we summarized the recent investigations of brusatol as an experimental therapeutic for human malignancies, such as leukemia, lung cancer, pancreatic cancer and brain tumor. We also discussed the molecular target brusatol, with a focus on the Nuclear factor erythroid 2-related factor 2 (NRF2)-guided gene transcription, as well as glutathione de novo synthesis. Further, we discussed the challenges and future applications of brusatol for cancer therapy. Conclusion In conclusion, we believe increasing evidences have shown the value of brusatol as a novel strategy for cancer treatment, which may indicate future drug development and clinical translation.