T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy that presents with poor prognosis. Treatment relies on the application of aggressive therapies that produce deleterious side-effects, justifying the quest for novel, more efficient and selective molecular targeting agents. Mutations leading to abnormal Notch-1 activity are present in more than half of the T-ALL patients, underscoring the potential therapeutic relevance of targeting Notch-1 inhibition and further reinforcing the need to better comprehend the mechanisms by which Notch-1 drives T cell leukemogenesis. Clinical application of γ-secretase inhibitors to block Notch signaling in T-ALL revealed new challenges that involve improvement of the therapeutic benefit and reduction of intestinal toxicity. Here, we review the latest advances in the development and use of Notch antagonists and summarize the current knowledge on Notch function in T-ALL to understand how it may translate into novel therapeutic strategies that increment the efficiency of Notch inhibition.