Chronic myeloid leukemia cells are armed with several resistance mechanisms that can make current drugs ineffective. A better understanding of resistance mechanisms is yielding new approaches to management of the disease. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm the hallmark ofwhich, the breakpoint cluster region-Abelson(BCR-ABL) oncogene, has been the target of  tyrosine kinase inhibitors (TKIs), which have significantly improved the survival of patients with CML. However, because of an increase in TKI resistance, it is becoming imperative to identify resistance mechanisms so that drug therapies can be better prescribed and new agents developed. In this review, we discuss the various  BCR-ABL-dependent and-independent mechanisms of resistance observed in CML, and the range of therapeutic solutions available to overcome such resistance and to ultimately improve the survival of patients with CML.