Patients with chronic myeloid leukemia who fail to achieve timely treatment responses have a worse prognosis. Although many patients respond well to first-line treatment with imatinib, a significant proportion relapse or experience an inadequate response. Since effective alternative Bcr-Abl inhibitors are available (i.e., dasatinib or nilotinib), several regional groups have proposed milestones for imatinib failure or suboptimal response based on the achievement of specified levels of response within a defined treatment duration. A suboptimal response indicates that, although patients may continue to receive a benefit from continuing imatinib treatment at the assigned dose, long-term outcome may be better with an alternative strategy. The underlying mechanisms behind suboptimal responses are multifactorial and may differ from those causing relapse.