Chronic myeloid leukemia (CML), a clonal stem cell disorder, inevitably evolves into a blastic phase that is very resistant to treatment. Recent developments of a better understanding of molecular changes in CML have led to highly effective targeted therapy that can induce molecular remissions, many of which are long-lasting. It is expected that these approaches will eventually improve treatment of the blastic phase of this disease, the molecular changes during its evolution to blastic phase, and the potential for therapeutic interventions. We review the molecular biology and evolution of treatment of the blastic phase of CML.