The fundamental relevance of cell–cell fusion processes is well studied and involves the precise spatiotemporal coordination of fusion-competent cells and the orchestration of typical fusion stages, ultimately leading to the genesis of a functional new cellular entity. While most physiological cell fusion events culminate in the formation of a multinucleated non-dividing cell, whereby nuclei remain spatially distinct, non-physiological fusion events are frequently coupled with the merging and mixing of the parental genomes. Upon cell division, fusion-induced whole-genome doubling and centrosome amplification drive chromosomal instability linked with multipolar mitoses, chromosome mis-segregation, non-disjunction and structural-associated alterations. In this context, aberrant cell fusion events can accelerate genomic heterogeneity that can potentiate the risk of cancer development and further propel cancer evolution by producing genetically diverse progeny via sub-clonal expansion. In this chapter, we provide insights into how unscheduled cell fusion events rapidly drive cancer evolution by promoting genetic and epigenetic instability, thereby creating a tumour landscape in which intratumoural heterogeneity and phenotypic plasticity increase the acquisition of traits linked with therapy resistance, stemness and immune evasion.