Aneuploidy, a hallmark of cancer characterized by chromosome imbalances, drives tumorigenesis and facilitates cancer immune evasion. While high tumor aneuploidy is linked to immune checkpoint blockade (ICB) resistance and poor prognosis, evidence suggests that this resistance can be overcome through treatment intensification, for example, with the addition of ablative radiotherapy to ICB. In this Perspective, we argue that the predictive value of aneuploidy complements established biomarkers, such as tumor mutational burden (TMB) or programmed death ligand 1 (PD-L1) expression. We review contemporary methods for quantifying aneuploidy, explore novel approaches that target mitotic vulnerabilities in aneuploid tumors and highlight potential areas where aneuploidy-based stratification could be incorporated into ICB-based treatment paradigms across early-stage, locally advanced and metastatic cancers. Prospective trials incorporating aneuploidy-based stratification will be essential to validate its role in personalized cancer therapy.