The BCR–ABL tyrosine kinase has been implicated as the cause of Philadelphia chromosome (Ph 1)-positive leukemias. We report herein that CGP 57148, a selective inhibitor of the ABL tyrosine kinase, caused apoptosis specifically in bcr–abl-positive chronic myelogenous leukemia (CML) cells, K562 and KYO-1. Upon treatment with CGP 57148, CRKL, a specific substrate for BCR–ABL that propagates signals via phosphatidylinositol-3′ kinase (PI3K), was dephosphorylated, indicating inhibition of BCR–ABL tyrosine kinase at the cellular level. Likewise, MAPK/ERK, a downstream mediator of Ras, was also dephosphorylated. Caspase activation and cleavage of retinoblastoma protein (pRB) accompanied the development of CGP 57148-induced apoptosis. Inhibition of caspase suppressed apoptosis and the cleavage of pRB, and in turn arrested cells in the G 1 phase. These results indicate that CGP 57148 shows apoptogenic and anti-proliferative effects on bcr–abl-positive cells by blocking BCR–ABL-initiated signaling pathways.