A major question in human genetics concerns the relationship between the extra chromosome material in the Down syndrome (DS) and its effects. It is suggested here that a generalized disruption of evolved genetic balance in cells of affected individuals leads to decreased developmental and physiological buffering against genetic and environmental forces. Examples of consequences in DS of this model of disruption of homeostasis are presented: i) increased variance for metric traits, ii) amplified instability of developmental pathways, iii) reduced precision of physiological homeostatic controls, and iv) generalized increased morbidity. Evolution has selected for interacting systems. When this evolved balance is disrupted, as in autosomal aneuploidy, the organism is generally disrupted. The model emphasizes the role of environment in producing much of the DS phenotype. Traits less buffered than others in the general population are the ones most disturbed in DS and account for much of the DS phenotype.