Down syndrome (DS), which occurs once in every 800 births, is associated with a trisomy on locus 21. Among the many aberrations caused by DS, including shortened stature and distorted facies, are several blood dyscrasias, including childhood leukemias-namely, acute myeloid leukemia (AML) and acute lymphoblastic, or lymphocytic, leukemia (ALL). One focus of the diagnosis of ALL is to distinguish it from AML.The benefits of immunophenotyping extend to treatment as well. ALL is associated with an inherited trisomy 21 in DS children (ALL-DS) and with acquired trisomies, +21, 8, and 13, in non-DS children (ALL-NDS). The differences in treatment, outcome, and prognosis between ALL-DS and ALL-NDS can be attributed to the interaction of their respective trisomies with several genetic mutations, including one on the GATA1 growth factor transcription gene. Other mutations are the gene fusion at TEL/AML1, and a new mutation found, which labels the Janus Kinase gene or JAK2 as on oncogenic precursor, which when associated with the B-cell precursor gene or BCP is highly leukomogenic. The treatments for the 2 groups have been based on quality of risk, with ALL-DS children having the highest risk along with the poorest prognosis, but alterations in medication regimens have brought treatment outcomes to near equality. It is worthwhile to study the trisomy 21 because in the future it may provide an understanding of all blood dyscrasias.