In patients with chronic myeloid leukemia (CML), the hallmark Philadelphia chromosome is the marker of disease that can be detected by conventional metaphase cytogenetics, fluorescence in situ hybridization, or polymerase chain reaction. The current “gold standard” of treatment response is cytogenetic response. Cytogenetic response to imatinib is strongly associated with disease progression and survival. Various strategies aimed at improving cytogenetic response have been explored, such as escalation of imatinib and switching to the newer breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene (BCR-ABL) inhibitors dasatinib and nilotinib. Data from recent randomized trials of dasatinib and nilotinib as first-line therapy of newly diagnosed chronic-phase CML suggest that these agents are more effective than imatinib in achieving 6-month and 12-month complete cytogenetic responses. However, it is still too early to know whether or not this early response will translate into a long-term survival advantage. In addition, more sensitive assays to detect residual disease also may be associated with improved long-term outcomes. The deepest measure of response—a complete molecular response—may help identify patients who can stop taking imatinib for the short term, although the long-term consequences of this strategy remain unknown. Cancer 2011;. © 2011 American Cancer Society.