Chronic myeloid leukemia (CML) depends on the kinase activity of the BCR-ABL1 fusion protein. This dependency has led to the development of BCR-ABL1 inhibitors, such as imatinib, dasatinib, and nilotinib, which have proved to be highly efficacious treatments for CML. The European LeukemiaNet guidelines have established the importance of achieving a certain depth of response at different time points during imatinib therapy for patients with newly diagnosed CML in chronic phase. Patients who achieve a complete cytogenetic response by 12 months or a major molecular response by 18 months are classified as optimal responders and deemed to have excellent long-term outcomes. Conversely, failing to achieve such milestones is associated with an increased risk of worse long-term outcomes, such as loss of response, disease progression, or death. With ongoing treatment, patients not in complete cytogenetic response face a decreasing probability of ever achieving a complete cytogenetic response or major molecular response and increasing risk of disease progression. Available data therefore support treatment recommendations based on achieving defined levels of response within a specified duration of treatment. Recent data have shown that dasatinib and nilotinib used as frontline CML therapy result in higher response rates that are achieved at earlier time points compared with standard-dose imatinib therapy. Future analyses will need to determine whether these higher rates of deep and fast responses translate into improved long-term survival. Cancer 2011;. © 2011 American Cancer Society.