Since the report in 2004 that NOTCH1 is a commonly mutated gene in T-ALL [17], deciphering the molecular mechanisms behind NOTCH1 deregulation leading to normal T-cell transformation, and elucidation of NOTCH1 target genes involved in leukemia cell growth, have been the keystones for developing novel targeted therapies for T-ALL patients harboring NOTCH1 mutations. This evidence concerns the gene NOTCH1 and acute lymphoblastic leukemia.