Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a specific genetic lesion, the Philadelphia chromosome, harboring the BCR-ABL oncogene. Since then, it has become a paradigm for the discovery of molecular mechanisms and targeted therapeutic approaches in the field of hematologic neoplasias. The past 5 years or so have been particularly fruitful in the dissection of the signal transduction pathways abnormally activated in CML and in the translation of this knowledge to clinical practice. In this report, we discuss the biological basis for such translation and highlight the current and potential tools for the effective treatment of CML patients. The first part presents a review of the basic concepts on the biology of CML and their application to the design of targeted therapy. The mechanisms of action of the molecular-specific drugs currently used in clinical trials are discussed, with emphasis on the description of the most promising new compounds that are enhancing the potential for effective alternative or combination chemotherapy in CML. In the following section, we explain how molecular monitoring of response to imatinib mesylate in patients with CML can be used as a guide to clinical management. In particular, we discuss the relative value of regular quantitative RT/PCR and cytogenetic analyses, how responding patients should be monitored and managed, and how to investigate patients who are refractory or become resistant to imatinib treatment. In the last part of this report, a discussion on the possibility of managing CML with patient-specific strategies is presented. We review the current treatment options, highlight the factors impacting on decision making, discuss the range of possibilities for future therapeutic strategies and propose a systematic approach for individualizing treatment for patients in different disease categories.