Tetraploidy is an aneuploidy-permissive condition that can fuel tumorgenesis. The tip-over hypothesis of cytotoxic therapy sensitivity proposes that therapy is effective if it pushes a cell's aneuploidy above a viable tipping point. But elevated aneuploidy alone may not account for this tipping point. Tissue microenvironments that lack sufficient resources to support tetraploid cells can explain the fitness cost of aneuploidy. Raw materials needed to generate deoxynucleotides, the building blocks of DNA, are candidate rate-limiting factors for the evolution of high-ploidy cancer cells. Understanding the resource cost of high ploidy is key to uncover its therapeutic vulnerabilities across tissue sites with versatile energy supplies.