Infant acute lymphoblastic leukemia (ALL) is an aggressive malignancy that has historically been associated with a very poor prognosis. Despite large co-operative international trials and incremental increases in intensity of therapy, there has been no significant improvement in outcome over the last 3 decades. Using representative cases, we highlight the key differences between KMT2A-rearranged and KMT2A-germline infant ALL, and how advances in molecular diagnostics are unpicking …