The lessons learned from the remarkably successful use of the first-generation tyrosine kinase inhibitor (TKI) imatinib in patients with chronic myeloid leukemia resulted in a major paradigm shift in the treatment of many human cancers, and now further lessons are being learned from our enhanced understanding of the molecular mechanisms of resistance to imatinib and second-generation TKIs, particularly dasatinib and nilotinib. Although diverse mechanisms seem to be involved, the principal cause appears to be the emergence of point mutations in the Abl kinase domain that affect drug affinity and some of which impair the efficacy with which the drugs bind. Currently, > 50 different mutations have been identified, and the extent to which they confer resistance varies considerably. One of the more common mutations results from the substitution of isoleucine for threonine at Abl amino acid position 351, known as the T315I mutation. It appears that the precise position of the substitution within the kinase domain dictates the degree of resistance to TKIs, and patients with the T315I mutation develop almost complete resistance to imatinib, dasatinib, and nilotinib. Herein, we discuss the emerging strategies for circumventing resistance associated with the Bcr-Abl T315I mutation.