Despite its ubiquity in cancer, link with other pathologies, and role in promoting adaptive evolution, the effects of aneuploidy or imbalanced chromosomal content on cellular physiology have remained incompletely characterized. Significantly, it appears that the detrimental as well as beneficial effects of aneuploidy are due to the altered gene expression elicited by the aneuploid state. In this review we examine the correlation between chromosome copy number changes and gene expression in aneuploid cells. We discuss the primary effects of aneuploidy on gene expression and describe the cellular response to altered mRNA and protein levels. Moreover, we consider compensatory mechanisms that may ameliorate imbalanced gene expression and restore protein homeostasis in aneuploid cells. Finally, we propose a novel hypothesis to explain the hitherto enigmatic abundance compensation of proteins encoded on supernumerary chromosomes.