Chronic myeloid leukemia is defined by the acquired genetic mutation, t(9;22), which leads to the fusion-protein BCR-ABL. Prior to the development of imatinib mesylate (Gleevec), treatment was limited and provided only limited survival benefit. Imatinib has dramatically changed the course of the disease and has led to the significantly prolonged survival in the majority of patients. However, there is growing concern for resistance to imatinib and to subsequent second generation tyrosine kinase inhibitors (dasatinib and nilotinib) due to the T315I mutation. With no currently approved effective treatment for TKI-resistant CML with the T315I mutation, molecularly-based, targeted drug development has focused on several strategies to overcome resistance. In this review, we describe agents which overcome the T315I mutation, as well as native BCR-ABL, via several mechanisms, including increased degradation of BCR-ABL, optimization of direct inhibition of the BCR-ABL kinase, inhibition of BCR-ABL-mediated cell growth via interruption of the BCR-ABL-mediated transcription, protein synthesis or post-translational modification, all of which lead to decreased proliferation and malignant cell death.