Until recently, pediatric Philadelphia chromosome-positive (Ph(+)) acute 
lymphoblastic leukemia (ALL) was associated with an extremely poor outcome when 
treated with chemotherapy alone, and only modest survival benefits were obtained 
with the widespread use of hematopoietic stem cell transplantation (HSCT). The 
development of first-generation (imatinib) and second-generation (dasatinib and 
nilotinib) tyrosine kinase inhibitors (TKIs) that target the BCR-ABL1 fusion 
protein produced by the Ph chromosome revolutionized the treatment of chronic 
myelogenous leukemia (CML). The Children's Oncology Group (COG) AALL0031 trial 
showed that the addition of imatinib to intensive chemotherapy did not cause 
increased toxicity and resulted in 3-year event-free survival rates that were 
more than double those of historical control data from the pre-imatinib era. 
These findings create a new paradigm for integrating molecularly targeted agents 
with conventional chemotherapy and call for a reassessment of the routine use of 
HSCT for children and adolescents with Ph(+) ALL. Second-generation TKIs have 
theoretical advantages over imatinib, and are now being tested in Ph(+) ALL. The 
focus of contemporary trials is to define the optimal use of chemotherapy, HSCT, 
and TKI in Ph(+) ALL. In the coming years, it is anticipated that additional 
agents will become available to potentiate TKI therapy and/or circumvent TKI 
resistance in Ph(+) ALL. Recent genomic studies have identified a subtype of 
high-risk pediatric B-cell-precursor ALL with a gene-expression profile similar 
to that of Ph(+) ALL, suggestive of active kinase signaling. Many of these 
Ph-like ALL cases harbor chromosome rearrangements and mutations that 
dysregulate cytokine receptor and kinase signaling, and these leukemias may also 
be candidates for TKI therapy.