The study of rare cancers, including retinoblastoma, angiosarcoma, and vaginal clear cell carcinoma, has contributed greatly to our understanding of cancer mechanisms. Infants with leukemia may represent another important rare group. The majority of infants with leukemia have MLL gene rearrangements in their leukemia cells, and there is unequivocal laboratory evidence that these arise in utero. There is increasing evidence that environmental and genetic factors may contribute to the risk of MLL-defined infant leukemias. Because the infant exposure experience is only a small window in comparison to that of an individual who develops a malignancy in middle or late age, the pivotal factors responsible for this genetic anomaly may be easier to identify. With the largest case-control study of infant leukemia ever conducted underway in the Children's Oncology Group (COG AE24), there is a unique opportunity to integrate epidemiological data with laboratory data on MLL status and genotype.