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harvard.edu Acute lymphoblastic leukemia is the most common malignancy in children. Although it is now curable in 80–90 % of cases, patients withT-cell acute lymphoblastic leukemia (T-ALL) experience a higher frequency of induction failure and early relapse. Despite aggressive treatment approaches, including transplantation and new salvage regimens, most children with relapsed T-ALL will not be cured. As such, we are in need of new targeted therapies for the disease. Recent advances in the molecular characterization ofT-ALL have uncovered a number of new therapeutic targets. This review will summarize recent advancements in the study of inhibiting the NOTCH1, PI3K–AKT, and Cyclin D3:CDK4/6 pathways as thera-peutic strategies for T-ALL. We will focus on pre-clinical studies supporting the testing of small-molecule inhibitors targeting these proteins and the rationale of combination thera-pies. Moreover, epigenetic approaches to modulate T-ALL are rapidly emerging. Here, we will discuss the data supporting the role of bromodomain and extra-terminal bromodomain inhibitors in human T-ALL. Keywords:T-cell acute lymphoblastic leukemia, NOTCH1, cyclins, cyclin-dependent kinases, PI3K/AKT/mTOR, PI3