The approval of dasatinib and nilotinib for first line treatment of chronic myeloid leukemia (CML) in chronic phase (CP) opened new therapeutic options. However, their role in this setting is yet undefined and additionally recent landmark studies have laid ground to re-discuss which response milestones are relevant for treatment guidance. Thus, updated data on these issues at last year’s ASH meeting were expected to potentially hint to what the new management standards might be. This short review briefly summarizes the respective evidence for (a) the outcome predictive value of early and deep molecular responses, (b) the superiority of second generation tyrosine kinase inhibitors (TKIs) to imatinib with regard to cytogenetic and molecular response rates, (c) the (yet) lacking proof of a survival benefit of second generation TKIs and (d) the role of new TKIs and alternative treatment strategies. Chronic myeloid leukemia (CML) has become a paradigm for targeted medicine; however, despite their impressive therapeutic success, TKIs offer disease control rather than disease eradication. The development of second generation TKIs broadened therapeutic options and consecutively disease management recommendations focused on response monitoring to guide change of treatment upon patient’s individual failure to respond. This short review will focus on ASH updates on second generation TKIs in first line treatment, potential future definitions of response milestones, and briefly on new TKIs and alternative TKI treatment concepts.