Well-defined, distinctive phenotypic features and natural history characterize Down syndrome, the most frequent form of developmental disability caused by a microscopically demonstrable chromosomal aberration. Triplicate state or trisomy of all or a portion of chromosome 21 causes Down syndrome. There are 3 genetic mechanisms leading to Down syndrome, or trisomy 21: nondisjunction, translocation, and mosaic. With advances in prenatal testing techniques, the diagnosis can occur before birth. This article explores the embryology and pathogenesis of Down syndrome and its multisystemic effects on the newborn. Specific attention is paid to presentation, clinical features, physical assessment, and family support. Recurrence risk and genetic counseling are discussed including the relationship of the risks and benefits of performing diagnostic procedures. In addition, this article reviews the management of healthcare needs for newborns with Down syndrome and the implications for nursing care.