Significant advances in the treatment of Philadelephia chromosome (Ph)- or BCR-ABL-positive acute lymphocytic leukemia (ALL) have been made since the discovery of the selective ABL tyrosine kinase inhibitors (TKIs). Whereas the outcome with standard chemotherapy was previously dismal, incorporation of imatinib mesylate into frontline therapy has improved relapse-free and overall survival. The benefit of imatinib extends particularly to instances where allogeneic stem cell transplantation in first complete remission is prohibited by older age, comorbidities, or lack of a suitable donor. However, the emergence of resistance to imatinib presents new therapeutic challenges. The development of novel TKIs with enhanced inhibitory potency against ABL and other kinases may further improve on the results observed with imatinib. Optimal use of these novel agents in the treatment schema of Ph(+) ALL will be paramount in ensuring continued success in the eradication of this disease. Herein, the new approaches to the management of Ph(+) ALL are reviewed.