This chapter explores both the normal physiological roles of cell fusion and its pathological implications in cancer. We focus on the emerging concept of fusion-induced polyploidy and senescence as a “double-edged sword”—a process that can suppress malignancy through growth arrest yet also promote tumor progression when polyploid cells escape senescence and acquire stem-like properties. In addition, we examine the interconnection between polyploidy and senescence, highlighting their similarities, differences, and dynamic interplay. Special attention is given to the molecular signaling pathways governing these processes, with particular emphasis on the central role of mTOR and the regulatory functions of long noncoding ribonucleic acids (lncRNAs). We also discuss how these insights inform potential therapeutic strategies, including the use of senolytic agents, the modulation of the senescence-associated secretory phenotype (SASP), and inhibitors targeting mTOR or mitotic regulators. Finally, we outline key unanswered questions in the field, emphasizing the need for reliable biomarkers to identify fusion-derived hybrids and for a deeper mechanistic understanding of cell fusion-derived polyploidy and senescence. A more comprehensive grasp of these mechanisms may pave the way for novel therapeutic approaches aimed at limiting tumor plasticity, overcoming therapy resistance, and ultimately improving patient outcomes.