with resistance to the drug. This was rapidly followed by the clinical description of imatinib resistant cells in patients, which has resulted in efforts to better understand the biology behind these observations. Assessments of therapeutic response of imatinib in patients with CML are based upon meeting hematologic, cytogenic and molecular milestones. Patients that fail to achieve defined responses at predefined time points are described as primarily resistant to therapy, and those losing previously obtained milestones in disease regression are termed secondarily resistant. Before a conclusion is drawn, it is important to consider that retrospective data has showed a high incidence of imatinib non-compliance in CML patients and this could lead to undesired clinical outcomes. In general, imatinib resistance can be subdivided into Bcr-Abl dependent and independent mechanisms. Bcr-Abl dependent mechanisms include over expression or amplification of the Bcr-Abl gene and point mutations within the Bcr-Abl kinase domain that interfere with imatinib binding. Bcr-Abl independent mechanisms include factors influencing the concentration of imatinib within the cell, for example by alterations in drug influx and efflux and activation of Bcr-Abl independent pathways, such as members of the Src kinase family. Imatinib resistance can also be produced by other mechanisms that will not be mentioned here as the importance of those mechanisms still remain a question due to lack of clinical data. Bcr-Abl dependent mechanisms of resistance Bcr-Abl duplication The first reports of resistance to imatinib described a development of oncogene amplification. That is, the gene that encodes for the pathogenic Bcr-Abl tyrosine kinase is duplicated in the DNA sequence, leading to higher expression of the pathogen. Increasing the imatinib dose could surmount this kind of resistance, provided that severe or intolerable adverse effects are not produced. Bcr-Abl mutation Point mutations can cause amino acid substitutions inside the kinase domain of the Bcr-Abl protein and disrupt the binding site of imatinib on the tyrosine kinase, resulting in a loss of sensitivity to the drug. These mutations normally affect the structure of the Bcr-Abl protein, leading either to interruption of critical contact points between the drug and the Bcr-Abl protein or induction of a conformational change, resulting in a protein that imatinib is unable to bind to. Mutational frequencies appear to increase as the disease, CML, progresses from chronic phase to the blast phase. The most important mutations are the P-loop mutations and the T315I mutation. Mutations on other sites of the kinase have