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The <i>KMT2A</i> (formerly <i>MLL</i>) encodes the histone lysine-specific N-methyltransferase 2A and is mapped on chromosome 11q23. <i>KMT2A</i> is a frequent target for recurrent translocations in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Over 90 <i>KMT2A</i> fusion partners have been identified until now, including the most recurring ones—<i>AFF1</i>, <i>MLLT1</i>, and <i>MLLT3</i>—which encode proteins regulating epigenetic mechanisms. The presence of distinct <i>KMT2A</i> rearrangements is an independent dismal prognostic factor, while very few <i>KMT2A</i> rearrangements display either a good or intermediate outcome. <i>KMT2A-</i>rearranged (<i>KMT2A</i>-r) ALL affects more than 70% of new ALL diagnoses in infants (<1 year of age), 5–6% of pediatric cases, and 15% of adult cases. <i>KMT2A</i>-rearranged (<i>KMT2A</i>-r) ALL is characterized by hyperleukocytosis, a relatively high incidence of central nervous system (CNS) involvement, an aggressive course with early relapse, and early relapses resulting in poor prognosis. The exact pathways of fusions and the effects on the final phenotypic activity of the disease are still subjects of much research. Future trials could consider the inclusion of targeted immunotherapeutic agents and prioritize the identification of prognostic factors, allowing for the less intensive treatment of some infants with <i>KMT2A</i> ALL. The aim of this review is to summarize our knowledge and present current insight into the mechanisms of <i>KMT2A</i>-r ALL, portray their characteristics, discuss the clinical outcome along with risk stratification, and present novel therapeutic strategies.