The advent of the Bcr-Abl selective tyrosine kinase inhibitor imatinib mesylate (Glivec, Gleevec, Novartis, East Hanover, NJ) has substantially changed the treatment landscape for chronic myelogenous leukemia (CML). However, some patients, primarily those with advanced disease, are either initially refractory to imatinib or eventually develop imatinib resistance. Imatinib resistance or intolerance frequently depends on the re-emergence of Bcr-Abl kinase activity, but can also indicate Bcr-Abl-independent disease progression. Results from phase II/III trials suggest rates of resistance and relapse correlate with stage of disease and with the monitoring parameters: hematologic, cytogenetic, and molecular responses. To date, more than 40 different point mutations that code for distinct single amino acid substitutions in the Bcr-Abl kinase domain have been isolated from imatinib-resistant patients. These mutations affect amino acids involved in imatinib binding or in regulatory regions of the Bcr-Abl kinase domain, resulting in decreased sensitivity to imatinib while retaining aberrant kinase activity. Early mutation detection may aid in risk stratification and molecular-based treatment decisions. To overcome imatinib-resistant disease, novel tyrosine kinase inhibitors with activity against imatinib-resistant mutations and/or with inhibition of alternative pathways, such as Src activation, have recently been developed. Additional strategies include imatinib dose escalation, combination therapy, and treatment interruption to stop clonal selection of resistant cells.