Tyrosine kinase inhibitor (TKI) treatment targeting breakpoint cluster region-Abelson murine leukemia virus, the cause of chronic myeloid leukemia (CML), has revolutionized therapy for patients with this disease. The majority of patients with CML maintain favorable responses with long-term imatinib therapy; however, the availability of the second-generation TKIs nilotinib and dasatinib limits the need for patients intolerant to imatinib to continue with therapy. Unfortunately, there is currently no standard definition of intolerance to imatinib. Common Toxicity Criteria for grading adverse events, designed to identify acute toxicities, are often used to determine intolerance. However, because CML therapies are long-term, patient quality of life may provide a better measure of true intolerance. Several general methods of quantifying patient quality of life are in use for patients with CML, and a CML-specific variant of the M. D. Anderson Symptom Inventory is in development. An appropriate and consistent definition of intolerance will provide clinicians with an algorithm for managing their patients with severe or chronic adverse events during treatment with imatinib. As more long-term data become available for newer TKIs, the definition of intolerance in the context of CML treatment will continue to evolve to maximize the likelihood of durable responses and superior quality of life for patients.