Chronic Myeloid Leukaemia is a myeloproliferative disorder driven by the t(9;22) chromosomal translocation coding for the chimeric protein BCR-ABL. CML treatment represents the paradigm of molecular therapy of cancer. Since the development of the tyrosine kinase inhibitor of the BCR-ABL kinase, the clinical approach to CML has dramatically changed, with a stunning improvement in the quality of life and response rates of patients. However, it remains clear that tyrosine kinase inhibitors (TKIs) are unable to target the most immature cellular component of CML, the CML stem cell. This review summarizes new insights into the mechanisms of resistance to TKIs.