Genomic analyses have revolutionized our understanding of the biology of acute lymphoblastic leukemia. These findings have resulted in a revision of the classification of all and incorporation of genomics into diagnosis and risk stratification. By contrast, advances in understanding of the basis of lineage ambiguous leukemia have been less satisfactory. Such leukemias commonly have a dismal prognosis and are classified by pathologic criteria that do not reflect disease biology or offer treatment options. In this talk I will describe advances in our understanding of such leukemias from genomic, experimental and mechanistic studies over the last decade that continue today. These studies demonstrate the power of integrated bulk and single cell genomic, xenograft and engineered mouse models to delineate new subtypes of leukemia that transcend conventional pathologic criteria, and show that the interplay of oncogene deregulation in hematopoietic progenitor subsets is critical to driving leukemogenesis. These studies not only shed light on the molecular pathogenesis of leukemia, but have direct implications for diagnostic classification and therapeutic targeting.