Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). For patients with CML, failure on standard-dose imatinib therapy (400 mg daily), imatinib dose escalation (600-800 mg daily) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients who experience drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutation status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse-event tolerance, and risk factors.