Despite the clinical efficacy achieved with frontline therapies for BCR-ABL-positive disease, such as imatinib and second-generation ABL inhibitors like nilotinib or dasatinib that were originally designed to override insensitivity to imatinib, drug resistance still remains a challenge, especially for patients with advanced-stage chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. The discovery of BCR-ABL point mutations has been a great asset to furthering our understanding of a major cause of drug resistance, as has discovery of multidrug resistance proteins, dysregulation of signaling molecules downstream of BCR-ABL, and insights into the underlying causes of stromal-mediated chemoresistance. Such elucidation of mechanisms of resistance associated with leukemic cell survival is essential for the optimization of current therapies and enhancement of patient survival via delaying or preventing disease recurrence. Here, we present an overview of the use of nilotinib in combination with other agents against BCR-ABL-positive leukemia, as well as solid tumors, for the purpose of increasing clinical efficacy and overriding drug resistance.