Why do trisomies, duplications, and other chromosomal abnormalities that alter gene copy number often have a negative effect on the normal development or physiology of an organism? This is particularly intriguing because in many species, aneuploidy is detrimental or lethal, while polyploidy is tolerated or even beneficial. The answer probably differs in each case, but is probably related to the concept of gene balance, which can be summarized as follows: genes, and the proteins they produce, have evolved to function in complex metabolic and regulatory networks. Some of these networks function best when certain enzymes and regulators are present in specific ratios to each other. Increasing or decreasing the gene copy number for just one part of the network may throw the whole network out of balance, leading to increases or decreases of certain metabolites, which may be toxic in high concentrations or which may be limiting in other important processes in the cell. The activity of genes and metabolic networks is regulated in many different ways besides changes in gene copy number, so duplication of just a few genes will usually not be harmful. However, trisomy and large segmental duplications of chromosomes affect the dosage of so many genes that cellular networks are unable to compensate for the changes and an abnormal or lethal phenotype results.