The introduction of imatinib mesylate (IM) has revolutionized the therapy of chronic myelogenous leukemia (CML) and changed dramatically the therapeutic strategies in this malignant disease. After the establishment of its success in patients refractory to standard treatments, IM has shown its superiority in terms of cytogenetic response in previously untreated patients and became the first line therapy in the majority of patients with CML. However, it is currently unknown if IM will have a curative potential in CML, a potential which has been shown only for allogeneic stem cell transplantation to date. The recent description of the development of resistance to IM and the discovery of the underlying Abl-kinase mutations as a principal mechanism of resistance prompted a major research effort to understand the pathophysiology of the resistance phenomenon and stimulated the implementation of new algorithms for the treatment.