Two hypotheses exist to explain the Down syndrome (DS) phenotype. The "gene dosage effect" hypothesis states that the phenotype is a direct result of the cumulative effect of the imbalance of the individual genes located on the triplicated chromosome or chromosome region. In a nut shell, the phenotype results directly from the overexpression of specific chromosome 21 genes. The "amplified developmental instability" hypothesis contends that most manifestations of DS may be interpreted as the results of a non-specific disturbance of chromosome balance, resulting in a disruption of homeostasis. This hypothesis was proposed in an attempt to explain the similarities between the phenotypes of different aneuploid states and the observation that all of the phenotypic traits in DS are also seen in the general population but at lower frequency, with less severity and usually only present as a single trait. Herein, we review recent data and present evidence to support the theory that the phenotypic traits of aneuploid syndromes, and DS in particular, result from the increased dosage of genes encoded on the triplicated chromosome.