Imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, some patients may experience resistance or intolerance to imatinib over time. For these patients, two excellent therapeutic options are available. Dasatinib, approved in 2006 for the treatment of patients with CML in all phases who experience imatinib resistance or intolerance, has displayed significant efficacy, with a 2-year follow-up showing durable hematologic and cytogenetic responses, as well as prolonged progression-free and overall survival. Nilotinib was approved in 2007 for the treatment of patients with CML in chronic phase or CML in accelerated phase, resistant or intolerant to prior therapy including imatinib, based on strong efficacy as well as a favorable safety profile. Several factors, including mutation status, patient history, and existing comorbidities can impact the decision to use dasatinib or nilotinib, or pursue other options such as allogeneic stem cell transplant. The purpose of this review article is to shed light on a further consideration when deciding which agent to use, based on the efficacy and safety of dasatinib and nilotinib. This consideration involves the differences in both the imatinib-resistant and -intolerant patients enrolled in the pivotal studies for each agent, as well as other trial criteria.