The molecular mechanisms underlying the specific traits in individuals with Down syndrome (DS) have been postulated to derive either from nonspecific perturbation of balanced genetic programs, or from the simple, mendelian-like influence of a small subset of genes on chromosome 21. However, these models do not provide a comprehensive explanation for experimental or clinical observations of the effects of trisomy 21. DS is best viewed as a complex genetic disorder, where the specific phenotypic manifestations in a given individual are products of genetic, environmental and stochastic influences. Mouse models that recapitulate both the genetic basis for and the phenotypic consequences of trisomy provide an experimental system to define these contributions.