Bcr-Abl tyrosine-kinase inhibitors (TKI) are the first-line therapy for most patients with chronic myelogenous leukemia (CML). More than 90% of CML cases are caused by a chromosomal abnormality that results in the formation of a so-called Philadelphia chromosome. This abnormality was discovered by Peter Nowell in 1960 and is a consequence of fusion between the Abelson (Abl) tyrosine kinase gene at chromosome 9 and the break point cluster (Bcr) gene at chromosome 22, resulting in a chimeric oncogene (Bcr-Abl) and a constitutively active Bcr-Abl tyrosine kinase that has been implicated in the pathogenesis of CML. Compounds have been developed to selectively inhibit the tyrosine kinase. Before the 2001 U.S. Food and Drug Administration (FDA) approval of imatinib, no drugs were available to alter the natural progression of CML. Only cytotoxic drugs such as busulfan, hydroxyurea or interferon-alpha (rIFN-α) were utilized. Even though the first Bcr-Abl TK inhibitor was named "the magic bullet" to cure cancer by Time magazine, a second generation of Bcr-Abl TKI was subsequently developed to combat the initial resistance that emerged. New forms of resistance can arise as: missense mutations within the Abl kinase domain, over-expression of Bcr-Abl, increased production of transmembrane plasma proteins, or the constitutive activation of downstream signaling molecules such as Src-family kinases. History CML has a well defined molecular target and relatively selective therapies aimed at that target, which is not the case for the majority of cancers and chemotherapies today. Bcr-Abl was regarded as highly attractive target for drug intervention since the Bcr-Abl fusion gene encodes a constitutively activated kinase. Drug discovery that specifically targeted the ATP binding site of a single kinase was regarded as quite a challenging task since hundreds of protein kinases were known in the human genome. In the presence of TKI the binding of ATP is blocked, phosphorylation is prevented and Bcr-Abl expressing cells either have a selective growth disadvantage or undergo apoptotic cell death. Due to increasing resistance and intolerance to imatinib efforts were made to develop new drugs that could inhibit the Bcr-Abl tyrosine kinase. This led to the discovery of second generation drugs. While drug screening was used to develop imatinib, second generation TKI's were developed with rational drug design approach due to increased knowledge in structural biology of the Bcr-Abl tyrosine kinase. First generation Imatinib (STI571) Imatinib (Gleevec) was discovered in 1992 and is regarded as first generation drug since it is the