Chronic myeloid leukemia (CML) is arguably the best understood of all human 
malignancies. Its origins in the hematopoietic stem cell can be traced to a 
reciprocal translocation involving chromosomes 9 and 22, dubbed the Philadelphia 
chromosome, which is observed in essentially all patients. The resulting fusion 
gene, BCR/ABL, encodes an activated tyrosine kinase that can act alone to induce 
a CML-like syndrome in mouse models. These animal models have validated BCR/ABL 
as a target for the development of specific pharmaceutical inhibitors. The 
kinase inhibitor imatinib mesylate (Gleevec) is highly specific, effective, and 
minimally toxic, but may not effect cures as a single agent, particularly in 
patients with accelerated and blast-phase disease. Resistance to imatinib can 
confound therapy. Surprisingly, a high percentage of resistant cases manifest 
intact or augmented BCR/ABL signaling, suggesting that this oncoprotein, or 
signaling pathways emanating from it, remain viable targets. Combination 
chemotherapy is under active investigation, and among the most compelling 
strategies is dual treatment with agents that both target BCR/ABL signal 
transduction. BCR/ABL activates Ras, and compounds designed to antagonize Ras 
function called farnesyl transferase inhibitors (FTIs) have shown potent 
activity in vitro and in animal models of BCR/ABL-induced leukemia. Initial 
clinical trials in patients with refractory acute myeloid leukemia and CML in 
blast crisis have shown significant activity, suggesting that trials combining 
imatinib and FTIs are warranted.