T-cell acute lymphoblastic leukemia (T-ALL) is a form of pediatric leukemia that is thought to be caused by approximately 12 distinct chromosomal translocations that lead to aberrant expression of as many different cellular genes. Development of novel, rational therapies against such a diverse set of mechanistic targets has thus been a formidable challenge. Recent studies, however, have identified a large fraction of T-ALL cases carrying mutations in one of these genes, Notch1, suggesting for the first time that many cases may share a common pathogenic etiology, and perhaps may allow the development of targeted therapies that benefit the majority of patients with this disease.