A 44-year-old woman with a prior history of myxoid liposarcoma who was previously treated with radiation, chemotherapy, and resection, was admitted with syncope and pancytopenia. She was diagnosed with a high-grade therapy-related myelodysplastic syndrome and treated with decitabine. Her disease soon progressed to overt acute myeloid leukemia (AML). She was treated with cytotoxic chemotherapy including cytarabine and topotecan, but she was not a candidate for further anthracycline exposure given her prior treatment for sarcoma and concern for cardiotoxicity. Her AML was refractory to two sequential induction regimens. Given that targeted genomic sequencing had revealed a BRAF V600E mutation with a high allelic fraction, she was then placed on combined targeted BRAF/MEK therapy with dabrafenib and trametinib for her refractory disease. This resulted in a dramatic response with clearance of circulating myeloblasts, restoration of normal hematopoiesis, a significant decrease in marrow leukemic burden, and a concordant decrease in the BRAF V600E allelic burden. The response was transient, however, with a rapid increase in circulating blasts a few weeks later. At the time of subsequent progression, four separate KRAS mutations were identified. She died approximately 4 months after her diagnosis from rapidly progressive AML.