Imatinib mesylate (Gleevec) (formerly STI571) has secured a definitive role in the treatment of chronic myeloid leukemia (CML) due to its specificity and efficacy. Although some patients become resistant to the drug, it may still be possible to control the leukemia with imatinib-containing regimens. Front-line treatment with such combinations may indeed minimize the risk that resistance, and hence relapse, occurs. In this review, we discuss the published data on in vitro studies that address this question in a variety of models, and attempt to predict efficacious combinations for future clinical trials. These represent regimens where imatinib is combined with conventional chemotherapeutic drugs or with inhibitors of other key signal transduction molecules that may be preferentially activated in CML cells.