In patients with chronic myelogenous leukemia (CML) treated at diagnosis with the standard therapy consisting of imatinib, 400 mg once daily, the failure to achieve a complete cytogenetic response (CCyR) within 12 months from the start of therapy has been shown to be associated with an increased risk of progression and an overall inferior survival. Experts of the European LeukemiaNet and NCCN have indicated what degrees of hematologic, cytogenetic, and molecular responses should be expected at definite time points for patients with CML to have the highest probability of experiencing the final optimal response, defined as the achievement of at least a complete hematologic response with a minor cytogenetic response after 3 months; at least a partial cytogenetic response after 6 months; at least a CCyR after 12 months; and a major molecular response after 18 months of therapy. The last opportunity for a CCyR has been established at 18 months. Because the residual probability of attaining a CCyR is reduced for patients who do not experience a complete hematologic response by 3 months, any cytogenetic response by 6 months, or a major cytogenetic response by 12 months, these conditions are considered treatment failures. At this point, a change in therapy is highly recommended, such as second-line treatment with the second-generation tyrosine kinase inhibitors nilotinib or dasatinib and, in specific situations, a stem cell transplant. The loss of any grade of previously achieved cytogenetic response at any time point is also considered an imatinib failure demanding a change of therapy. Finally, intermediate gradations of response exist between optimal response and failure in which, although not totally compromised, the possibilities of achieving an optimal response later are decreased. The best therapeutic strategies to be followed in these intermediate situations, called suboptimal responses, have not been clearly established and are still under clinical investigation, but for the moment, a change of therapy is not required.