Myeloid blast-phase chronic myeloid leukemia (MBP-CML) is a rare disease with a dismal prognosis. It is twice as common as lymphoid blast-phase CML, and its prognosis is poorer. Despite the success with tyrosine kinase inhibitors in the treatment of chronic-phase CML, the same does not hold true for MBP-CML. In addition to the Philadelphia chromosome, other chromosomal and molecular changes characterize rapid progression. Although some progress in elucidating the biology of MBP-CML has been made, there is need to discover more in order to develop more satisfactory treatment options. Currently, most common treatment options include tyrosine kinase inhibitors (TKIs) as monotherapy or in combination with acute myeloid leukemia-based intensive chemotherapy regimens. Some patients may develop resistance to TKIs via BCR-ABL1-dependent or BCR-ABL1-independent mechanisms. In this paper, we provide an overview of the biology of MBP-CML, the current treatment approaches, and mechanisms of resistance to TKIs. In order to improve treatment responses in these patients, more emphasis should be placed on understanding the biology of myeloid blastic transformation in CML and mechanisms of resistance to TKIs. Although patient numbers are small, randomized clinical trials should be considered.