KMT2A rearrangements (KMT2A-r) are prominent drivers of aggressive acute leukemias, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and leukemias exhibiting mixed-lineage phenotypes, often referred to historically as ‘mixed lineage leukemia’. The gene discussed is KMT2A; the disease is acute lymphoblastic leukemia.