Imatinib mesylate (Gleevec) is a tyrosine kinase inhibitor currently used for treatment of BCR-ABL (Breakpoint Cluster Regionâ€“vabl ABelson murine Leukemia viral oncogene) Tyrosine Kinase (TK) positive leukemia, as well as GastroIntestinal Stromal Tumors (GIST). Imatinib represents one of the rare successful stories in drug development . Imatinib binds to the catalytic site of the kinase and traps it in an inactive conformation. This success was made possible through decades of intensive and collaborative research which led to discovery of the involvement of this protein kinase in tumor pathology. However, this success though impressive, was not immortal. A resistance to the drug developed. Drug resistance is often associated with chronic treatment with anticancer drugs and is likely due to the general genomic instability well documented in cancer. It has been shown that Activation Induced Cytidine Deaminase, AICD, the enzyme that converts cytidine to uridine, causing DNA breaks and hypermutations, also causes mutations in BCR-ABL TK resulting in Imatinib resistance. The recently revealed complexity of polyclonal resistance in patients with imatinib-resistant GIST, suggests that a single next generation drug is unlikely to inhibit all mutant clones in a given patient.