Most tyrosine kinase inhibitor (TKI)-associated adverse events are easily managed by symptomatic relief, although dose reductions or interruptions may be necessary in some patients. Long-term follow-up of early clinical trials has shown that the majority of imatinib-associated adverse events generally occur early, and the incidence decreases over the course of therapy, making imatinib the treatment of choice for long-term administration. A lack of patient adherence to imatinib, due to the occurrence of adverse events or for other reasons, can decrease response rates, and may cause resistance or disease relapse. Patient adherence to TKI therapies is a critical consideration for successful, long-term management of patients with chronic myeloid leukemia (CML). In patients who remain intolerant to imatinib, the differing tolerability profiles of second-generation TKIs should be considered when determining a therapeutic course of action. Throughout the course of therapy for CML, early and successful management of adverse events will increase dose optimization and patient adherence, and thereby optimize responses. Semin Hematol 46:S16-S21. (C) 2009 Elsevier Inc. All rights reserved.