Polyploidy, or whole-genome duplication (WGD), is a recurrent mutation both in cell lineages and over evolutionary time. By globally changing the relationship between gene copy number and other cellular entities, it can induce dramatic changes at the cellular and phenotypic level. Perhaps surprisingly, then, the insights that these events can bring to understanding other cellular features are not as well appreciated as they could be. In this review, we draw on examples of polyploidy from animals, plants and yeast to explore how investigations of polyploid cells have improved our understanding of the cell cycle, biological network complexity, metabolic phenotypes and tumor biology. We argue that the study of polyploidy across organisms, cell types, and time scales serves not only as a window into basic cell biology, but also as a basis for a predictive biology with applications ranging from crop improvement to treating cancer.