Abnormal activation of Notch1 plays pivotal roles in the molecular pathogenesis of human T-cell acute lymphoblastic leukemia (T-ALL). Activating Notch1 mutations present in over 60% of the T-ALL patients. However, so far, there is no therapy with little side effects that specifically targets the abnormally activated Notch1 pathway-induced T-ALL. The present study briefly reviewed the effects of abnormal activation of Notch1 in the pathogenesis of T-ALL, as well as the current approaches targeting Notch1 and its limitations, thus providing some guidance for the research and development of clinical therapies targeting T-ALL.