Whole-genome doubling (WGD), characterized by the duplication of an entire set of chromosomes, is commonly observed in various tumors, occurring in approximately 30–40% of patients with different cancer types. The effect of WGD on tumorigenesis varies depending on the context, either promoting or suppressing tumor progression. Recent advances in genomic technologies and large-scale clinical investigations have led to the identification of the complex patterns of genomic alterations underlying WGD and their functional consequences on tumorigenesis progression and prognosis. Our comprehensive review aims to summarize the causes and effects of WGD on tumorigenesis, highlighting its dualistic influence on cancer cells. We then introduce recent findings on WGD-associated molecular signatures and genetic aberrations and a novel subtype related to WGD. Finally, we discuss the clinical implications of WGD in cancer subtype classification and future therapeutic interventions. Overall, a comprehensive understanding of WGD in cancer biology is crucial to unraveling its complex role in tumorigenesis and identifying novel therapeutic strategies.