The current treatment of chronic myelogenous leukemia (CML) is one of the most successful examples of molecularly targeted therapy in cancer. The identification of the fusion oncogene BCR-ABL allowed the discovery of small molecule inhibitors of its tyrosine kinase activity which, in turn, have literally revolutionized the treatment of this disease. However, large part of a successful clinical management of CML relies on appropriate diagnosis, molecular monitoring and identification of mutations potentially leading to drug resistance. These issues are discussed here together with an overview on how patients treated with tyrosine kinase inhibitors should be monitored.