Despite the success with tyrosine kinase inhibitors (TKIs) in most patients with chronic myelogenous leukemia (CML), some patients still experience resistance or intolerance and need alternative therapies. Monitoring response to TKI therapy is a critical component of managing CML, and molecular response seems to be the most important milestone for predicting long-term outcomes. How best to assess response, including how to define treatment failure, and how monitoring should be conducted remain controversial. Strategies for overcoming imatinib resistance include increasing the imatinib dose or switching to a second-generation TKI. Another approach is to use higher doses of imatinib or second-generation TKIs up front to increase the rate of earlier responses, with the hope that this will translate into a reduced risk of resistance. Several investigational therapies are also being evaluated as a means of overcoming TKI resistance, including ponatinib (AP24534), omacetaxine, and bosutinib (SKI-606). Allogeneic hematopoietic stem cell transplantation has also shown efficacy in patients with imatinib-resistant disease. Alternatives to long-term TKI therapy that are currently being explored include discontinuation of treatment and eradication of minimal residual disease with investigational treatment regimens, such as those involving interferon, hydroxychloroquine, BCL6 inhibitors, and the smoothened antagonists LDF225 and BMS-833923.