Chromosomal instability (CIN) is a hallmark of cancer, characterized by chromosomal abnormalities such as deviations from the normal chromosome number or structural changes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to cells with abnormal chromosome numbers or structures. In normal cells, CIN is deleterious, causing DNA damage, proteotoxic stress, metabolic alterations, cell cycle arrest, and senescence. However, paradoxically, CIN is also a key feature of over 90% of solid tumors and blood cancers, enhancing tumor adaptation and resistance to therapies. This review explores the causes and consequences of CIN, its paradoxical nature, and its potential as a therapeutic target. CIN can be classified into numerical and structural forms, with numerical CIN involving gains or losses of whole chromosomes, and structural CIN involving rearrangements of chromosomal segments. The causes of CIN include replication stress, defective DNA repair, impaired sister chromatid segregation, aberrant centrosome number, and microtubule-kinetochore attachment errors. Replication stress and defective DNA repair mechanisms, such as the DNA damage response (DDR), play crucial roles in generating CIN. Impaired sister chromatid segregation, often due to cohesin complex dysfunction, can lead to chromosome missegregation. Aberrant centrosome number and microtubule-kinetochore attachment errors further contribute to CIN. The "just-right" model suggests that a moderate level of CIN can benefit tumor progression by increasing intratumor heterogeneity and adaptive resistance, while excessive CIN can induce tumor cell death. The review also discusses the multifaceted impacts of CIN on tumor biology, including DNA damage, proteotoxic stress, metabolic alterations, cell cycle arrest, senescence, and enhanced metastasis and drug resistance. Understanding the complex nature of CIN is crucial for developing effective anti-tumor treatments.Chromosomal instability (CIN) is a hallmark of cancer, characterized by chromosomal abnormalities such as deviations from the normal chromosome number or structural changes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to cells with abnormal chromosome numbers or structures. In normal cells, CIN is deleterious, causing DNA damage, proteotoxic stress, metabolic alterations, cell cycle arrest, and senescence. However, paradoxically, CIN is also a key feature of over 90% of solid tumors and blood cancers, enhancing tumor adaptation and resistance to therapies. This review explores the causes and consequences of CIN, its paradoxical nature, and its potential as a therapeutic target. CIN can be classified into numerical and structural forms, with numerical CIN involving gains or losses of whole chromosomes, and structural CIN involving rearrangements of chromosomal segments. The causes of CIN include replication stress, defective DNA repair, impaired sister chromatid segregation, aberrant centrosome number, and microtubule-kinetochore attachment errors. Replication stress and defective DNA repair mechanisms, such as the DNA damage response (DDR), play crucial roles in generating CIN. Impaired sister chromatid segregation, often due to cohesin complex dysfunction, can lead to chromosome missegregation. Aberrant centrosome number and microtubule-kinetochore attachment errors further contribute to CIN. The "just-right" model suggests that a moderate level of CIN can benefit tumor progression by increasing intratumor heterogeneity and adaptive resistance, while excessive CIN can induce tumor cell death. The review also discusses the multifaceted impacts of CIN on tumor biology, including DNA damage, proteotoxic stress, metabolic alterations, cell cycle arrest, senescence, and enhanced metastasis and drug resistance. Understanding the complex nature of CIN is crucial for developing effective anti-tumor treatments.