The introduction of tyrosine kinase inhibitors (TKIs) has fundamentally changed the management of chronic myeloid leukemia (CML). Disease progression to advanced phase (accelerated or blast phase) has been reduced to 1 to 1.5 % per year from more than 20 % per year in the pre-TKI era. However, once the disease has progressed to accelerated or blast phase, there is no consensus regarding optimal therapy. The prognosis of these patients is dismal with median survival ranging from 7 to 11 months. TKIs along with allogeneic hematopoietic cell transplantation are conventional strategies in managing these patients but there are very few long-term survivors. Advanced phase CML represents the new frontier for CML treatment where research is critically needed to improve patient outcomes.