Leukemia in infants is rare but generates tremendous interest due to its aggressive clinical presentation in a uniquely vulnerable host, its poor response to current therapies, and its unique biology that is increasingly pointing the way toward novel therapeutic approaches. This review highlights the key clinical, pathologic, and epidemiologic features of infant leukemia, including the high frequency of mixed lineage leukemia (MLL) gene rearrangements. The state of the art with regard to current approaches to risk stratified treatment of infant leukemia in the major international cooperative groups is discussed. Finally, exciting recent discoveries elucidating the molecular biology of infant leukemia are reviewed and novel targeted therapeutic strategies, including FLT3 inhibition and modulation of aberrant epigenetic programs, are suggested.