Alternative explanations for aneuploid phenotypes are evaluated according to clinical and experimental predictions. The additive hypothesis views the diverse manifestations of aneuploidy as the simple sum of individual gene dosage effects. The interactive hypothesis views aneuploid characteristics as network properties of genes within and outside the aneuploid segment. The importance and historical context of this debate are emphasized, and the 2 hypotheses are contrasted in terms of their experimental predictions and explanatory power. In particular, the concepts of colinearity and continuity derived from single gene action are explicitly examined in human aneuploidy with the conclusion they are likely to be false assumptions.