Chronic myeloid leukemia (CML) is characterized by the presence of the 
Philadelphia chromosome, which is associated with a balanced translocation 
involving chromosomes 9 and 22 to produce a fusion gene (bcr-abl) that gives 
rise to a constitutively activated Abl tyrosine kinase. This kinase led to the 
discovery of several small-molecule inhibitors, imatinib being the first and 
most successful of these. Resistance to imatinib results in some patients from 
Abl kinase point mutations. Overcoming imatinib resistance represents one of the 
biggest challenges facing clinicians in the modern management of CML. In this 
review, we discuss the current understanding of CML pathophysiology and 
mechanisms of imatinib resistance and how advancing this knowledge has led to 
the design of novel therapies in the area of blastic phase CML and Philadelphia 
chromosome-positive acute lymphoblastic leukemia with previous imatinib failure.