This review discusses the role of large genomic alterations in cancer evolution, focusing on mechanisms, impacts, and their interplay with physical and selective factors. Large genomic alterations include aneuploidy, whole genome duplications (WGD), and complex structural variants (SVs) such as chromothripsis, chromoplexy, and extrachromosomal DNA (ecDNA). These alterations affect multiple genes and have significant impacts on cellular fitness. Aneuploidy, caused by chromosomal instability (CIN), is common in cancers and can be episodic, reflecting past or ongoing CIN. WGD, which doubles the entire genome, is linked to increased CIN and poor survival. Complex SVs, such as chromothripsis and chromoplexy, generate massive, clustered rearrangements and oncogenic gene fusions. EcDNA, circular DNA molecules, act as mobile regulatory elements, enhancing oncogene transcription and mediating therapeutic resistance. These large-scale alterations often occur early in tumor evolution, driving tumor initiation and progression. The timing and frequency of these events are influenced by both physical and selective factors, and their impact on cellular fitness is complex. Understanding these alterations requires a combination of experimental systems, computational models, and single-cell analyses to disentangle the underlying mutational processes and their interactions.This review discusses the role of large genomic alterations in cancer evolution, focusing on mechanisms, impacts, and their interplay with physical and selective factors. Large genomic alterations include aneuploidy, whole genome duplications (WGD), and complex structural variants (SVs) such as chromothripsis, chromoplexy, and extrachromosomal DNA (ecDNA). These alterations affect multiple genes and have significant impacts on cellular fitness. Aneuploidy, caused by chromosomal instability (CIN), is common in cancers and can be episodic, reflecting past or ongoing CIN. WGD, which doubles the entire genome, is linked to increased CIN and poor survival. Complex SVs, such as chromothripsis and chromoplexy, generate massive, clustered rearrangements and oncogenic gene fusions. EcDNA, circular DNA molecules, act as mobile regulatory elements, enhancing oncogene transcription and mediating therapeutic resistance. These large-scale alterations often occur early in tumor evolution, driving tumor initiation and progression. The timing and frequency of these events are influenced by both physical and selective factors, and their impact on cellular fitness is complex. Understanding these alterations requires a combination of experimental systems, computational models, and single-cell analyses to disentangle the underlying mutational processes and their interactions.