Cell fusion is increasingly recognized as a critical event in cancer biology. The process has now been associated with diverse outcomes related to cancer pathophysiology, including tumor heterogeneity, metastasis, immune evasion, therapy resistance, and progression. Evidence from in vitro, in vivo, and clinical studies confirms that both homotypic (cancer–cancer) and heterotypic (cancer–non-cancer) fusion events result in hybrid populations with enhanced fitness. Comparable to what occurs in normal physiological conditions, fusion involves membrane priming, adhesion, merging, and post-fusion resetting. The process of fusion is driven by fusogens such as syncytin-1 and annexins, and it is influenced by external cues, including inflammation, hypoxia, viral infection, and therapeutic stress. Functionally, cell fusion boosts genomic instability and tumor plasticity, increases metastatic potential, allows for stem-like reprogramming, and aids in immune evasion. Clinically, hybrid cells could serve as reliable biomarkers for diagnosis, prognosis, and treatment stratification. Nevertheless, the dual function of fusion in tumor growth and normal physiology necessitates context-specific approaches. Unraveling the fusion machinery or leveraging fusion-induced immunogenicity might yield novel therapeutic opportunities. This chapter discusses the molecular, functional, and clinical aspects of cancer cell fusion, as well as its importance in cancer progression and therapy resistance.