In the emergence of resistance to imatinib, ABL-kinase inhibitor has become a significant problem despite the remarkable clinical results achieved with this drug in the treatment of chronic myeloid leukemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutation in the ABL-kinase domain. Persistent disease is another therapeutic challenge and may in part, be due to the inability of imatinib to eradicate primitive stem cell progenitors. A multitude of novel agents have been developed and shown efficacy in overcoming imatinib resistance.