Tyrosine kinase inhibitor (TKI) therapy has significantly changed the treatment paradigm for patients with chronic myeloid leukemia (CML). The first-generation inhibitor, imatinib, has demonstrated remarkable efficacy in most chronic-phase patients. Disease progression remains a significant risk for the first 2 to 3 years of TKI therapy, but the risk falls significantly thereafter. Early recognition of each individual's risk of progression may facilitate a customized approach to TKI therapy. Using such an approach, drug selection and treatment intensity would be adjusted on the basis of each patient's disease profile. Currently available prognostic indicators have limited value in the setting of the potent kinase inhibition afforded by TKIs. Furthermore, these indicators provide little guidance regarding optimal drug choice and dose intensity. In the future, assays that directly assess the efficacy of the protein-drug interaction, taking into account factors intrinsic to the patient and the amount of drug freely available in the plasma, are likely to be of greater value.