Chromosomal instability (CIN) generates continuously novel aneuploid genomes—unbalanced chromosome combinations that differ from the haploid chromosome set and its multiples. On one hand, this causes problems for cells, as high CIN and aneuploidy impair cellular proliferation by inducing multiple cellular stresses. At the same time, some genomes might provide an advantage under suboptimal conditions. However, what happens to cells that carry a mutation generating extremely high CIN? Are they sentenced to death, or can their instability help them to avert that fate? The elegant work from Ravichandran and colleagues (pp. 1485–1498) in this issue of Genes & Development exploits budding yeast to shed new light on cellular adaptations to CIN. The study presents exciting findings elucidating forces that shape aneuploid genomes in eukaryotic cells and likely influence karyotypic evolution in cancer cells.