The study investigates the natural diversity of *Saccharomyces cerevisiae* isolates to understand aneuploidy tolerance. It finds that aneuploidy, characterized by an imbalance in chromosome copy numbers, is common in natural isolates (around 20%), contrasting with the transient and costly nature of aneuploidy in laboratory strains. By generating a proteomic resource and integrating it with genomic and transcriptomic data from 796 euploid and aneuploid isolates, the researchers discover that natural isolates exhibit dosage compensation at the proteome level, with over 70% of proteins encoded on aneuploid chromosomes showing dosage compensation. This compensation is driven by increased protein turnover and the induction of the ubiquitin-proteasome system (UPS). The study highlights the role of protein turnover in mediating aneuploidy tolerance and underscores the importance of exploiting natural species diversity to gain insights into complex biological processes.The study investigates the natural diversity of *Saccharomyces cerevisiae* isolates to understand aneuploidy tolerance. It finds that aneuploidy, characterized by an imbalance in chromosome copy numbers, is common in natural isolates (around 20%), contrasting with the transient and costly nature of aneuploidy in laboratory strains. By generating a proteomic resource and integrating it with genomic and transcriptomic data from 796 euploid and aneuploid isolates, the researchers discover that natural isolates exhibit dosage compensation at the proteome level, with over 70% of proteins encoded on aneuploid chromosomes showing dosage compensation. This compensation is driven by increased protein turnover and the induction of the ubiquitin-proteasome system (UPS). The study highlights the role of protein turnover in mediating aneuploidy tolerance and underscores the importance of exploiting natural species diversity to gain insights into complex biological processes.