Imatinib mesylate (Gleevec) was developed as the first molecularly targeted therapy that specifically inhibits the BCR-ABL tyrosine kinase activity in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). Due to its excellent hematologic and cytogenetic responses, particularly in patients with chronic phase CML, imatinib has moved towards first-line treatment for newly diagnosed CML. Nevertheless, resistance to the drug has been frequently reported and is attributed to the fact that transformation of hematopoietic stem cells by BCR-ABL is associated with genomic instability. Point mutations within the ABL tyrosine kinase of the BCR-ABL oncoprotein are the major cause of resistance, though overexpression of the BCR-ABL protein and novel acquired cytogenetic aberrations have also been reported. A variety of strategies derived from structural studies of the ABL-imatinib complex have been developed, resulting in the design of novel ABL inhibitors, including AMN107, BMS-354825, ON012380 and others. The major goal of these efforts is to create new drugs that are more potent than imatinib and/or more effective against imatinib-resistant BCR-ABL clones. Some of these drugs have already been successfully tested in preclinical studies where they show promising results. Additional approaches are geared towards targeting the expression or stability of the BCR-ABL kinase itself or targeting signaling pathways that are chronically activated and required for transformation. In this review, we will discuss the underlying mechanisms of resistance to imatinib and novel targeted approaches to overcome imatinib resistance in CML.