Chronic myelogenous leukemia (CML), both myeloid and lymphoid blast-phase CML, and some cases of acute lymphoblastic leukemia make up the Bcr-Abl-positive leukemias. The chimeric bar-abl gene codes for a tyrosine kinase that is constitutively triggered in the leukemic cells and assumes the focal part in leukemogenesis. The increased activity of the Ras signaling pathway that leads to abnormal transduction of growth and survival signals has been demonstrated by hematologic malignancies, which include Bcr-Abl-positive leukemias. The tyrosine kinase inhibitor imatinib mesylate (STI571) and farnesyltransferase inhibitors (R115777, SCH66336) are some of the modern investigational therapeutic options that aim at these specific molecular defects of leukemic cells. These options inhibit the localization of Ras proteins to the cell membrane. In patients with Bcr-Abl-positive leukemias, the new agents combined with single-agent therapy might cause hematologic and cytogenetic remissions. However, molecular remissions are rare and there are chances of the development of resistance. As a result, a multifaceted therapeutic approach’s development is an intriguing aspect. A probable addition to the therapeutic arsenal is the arsenic trioxide (ATO), which has considerable activity in patients with relapsed and refractory acute promyelocytic leukemia. It is true that some of the molecular activities of ATO are particular to acute promyelocytic leukemia. Despite that, the arsenicals have an expansive assortment of antineoplastic properties. Such properties could be beneficial in combination therapy with agents that target particular molecular defects of Bcr-Abl-positive leukemias.