Compared with acute lymphoblastic leukemia (ALL) in older children, ALL in infants has a dismal outcome because rearrangements of the mixed-lineage leukemia (MLL) gene occur in about 80% of these patients, leading to an aggressive type of leukemia. With most recent therapies, about 50% long-term event-free survival is achieved, but early bone marrow relapse remains a major problem. Early intensification of chemotherapy and new innovative therapies are necessary to improve outcome. Bone marrow transplantation should be limited to a small subset of well-recognized ALL patients with a very poor prognosis. New genetic and epigenetic insights into the biology of MLL-rearranged ALL suggest new possibilities for therapies.