Aneuploidy, the presence of an abnormal number of chromosomes, has long been associated with cancer, but recent research suggests it can also suppress tumorigenesis in certain contexts. This review explores the mechanisms by which aneuploidy contributes to or inhibits tumor development. Aneuploidy arises from errors in chromosome segregation during mitosis, including defects in the mitotic checkpoint, chromosome cohesion, and multipolar spindle formation. These errors can lead to chromosomal instability (CIN), which increases the rate of chromosome gains and losses. While CIN is often linked to aneuploidy, the two are not synonymous. Aneuploidy can promote tumorigenesis by increasing the likelihood of cellular transformation, but it can also suppress tumor growth by inducing apoptosis or reducing the growth of preneoplastic cells. In mouse models, reduced levels of mitotic checkpoint components such as MAD1, MAD2, BUB1, and BUBR1 lead to increased aneuploidy and CIN, but not necessarily tumorigenesis. Some aneuploid cells are resistant to transformation, suggesting that additional mutations are required for tumorigenesis. Conversely, overexpression of checkpoint components like MAD2 can increase aneuploidy and tumorigenesis. Tetraploidy, a form of aneuploidy with four sets of chromosomes, can also drive tumorigenesis by increasing genomic instability. However, aneuploidy can act as a tumor suppressor in certain contexts, such as when it reduces the incidence of carcinogen-induced tumors or extends survival in mice lacking certain tumor suppressors. The role of aneuploidy in tumorigenesis depends on the cell type and genetic context. While aneuploidy can promote tumorigenesis by increasing the likelihood of mutations, it can also suppress tumor growth by inducing apoptosis or reducing the growth of preneoplastic cells. Understanding the mechanisms by which aneuploidy influences tumorigenesis is crucial for developing new therapeutic strategies. Future research should focus on identifying the genetic contexts in which aneuploidy promotes or suppresses tumorigenesis and developing models that accurately reflect the chromosomal instability seen in aneuploid cancers.Aneuploidy, the presence of an abnormal number of chromosomes, has long been associated with cancer, but recent research suggests it can also suppress tumorigenesis in certain contexts. This review explores the mechanisms by which aneuploidy contributes to or inhibits tumor development. Aneuploidy arises from errors in chromosome segregation during mitosis, including defects in the mitotic checkpoint, chromosome cohesion, and multipolar spindle formation. These errors can lead to chromosomal instability (CIN), which increases the rate of chromosome gains and losses. While CIN is often linked to aneuploidy, the two are not synonymous. Aneuploidy can promote tumorigenesis by increasing the likelihood of cellular transformation, but it can also suppress tumor growth by inducing apoptosis or reducing the growth of preneoplastic cells. In mouse models, reduced levels of mitotic checkpoint components such as MAD1, MAD2, BUB1, and BUBR1 lead to increased aneuploidy and CIN, but not necessarily tumorigenesis. Some aneuploid cells are resistant to transformation, suggesting that additional mutations are required for tumorigenesis. Conversely, overexpression of checkpoint components like MAD2 can increase aneuploidy and tumorigenesis. Tetraploidy, a form of aneuploidy with four sets of chromosomes, can also drive tumorigenesis by increasing genomic instability. However, aneuploidy can act as a tumor suppressor in certain contexts, such as when it reduces the incidence of carcinogen-induced tumors or extends survival in mice lacking certain tumor suppressors. The role of aneuploidy in tumorigenesis depends on the cell type and genetic context. While aneuploidy can promote tumorigenesis by increasing the likelihood of mutations, it can also suppress tumor growth by inducing apoptosis or reducing the growth of preneoplastic cells. Understanding the mechanisms by which aneuploidy influences tumorigenesis is crucial for developing new therapeutic strategies. Future research should focus on identifying the genetic contexts in which aneuploidy promotes or suppresses tumorigenesis and developing models that accurately reflect the chromosomal instability seen in aneuploid cancers.