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Simple Summary  Even though it is known that (cancer) cells can fuse, it is still less understood how (cancer) cells merge their plasma membranes, thereby giving rise to bi- and multinucleated hybrid cells. Cell-cell fusion is an energy-dependent process and so-called fusogens are a crucial type of membrane-bound proteins, which are mandatory for overcoming plasma membrane hybridization with associated energetic barriers. Viruses and fusogens of human endogenous retroviral elements are a natural reservoir of fusogenic particles and proteins that could cause bi- and multinucleation of cancer cells. Likewise, multinucleated giant cancer cells have been found in several cancers caused by oncogenic viruses suggesting a possible correlation between viruses and fusogens of human endogenous retroviral origin in cancer cell fusion.    Abstract  Cell fusion is a well-known, but still scarcely understood biological phenomenon, which might play a role in cancer initiation, progression and formation of metastases. Although the merging of two (cancer) cells appears simple, the entire process is highly complex, energy-dependent and tightly regulated. Among cell fusion-inducing and -regulating factors, so-called fusogens have been identified as a specific type of proteins that are indispensable for overcoming fusion-associated energetic barriers and final merging of plasma membranes. About 8% of the human genome is of retroviral origin and some well-known fusogens, such as syncytin-1, are expressed by human (cancer) cells. Likewise, enveloped viruses can enable and facilitate cell fusion due to evolutionarily optimized fusogens, and are also capable to induce bi- and multinucleation underlining their fusion capacity. Moreover, multinucleated giant cancer cells have been found in tumors derived from oncogenic viruses. Accordingly, a potential correlation between viruses and fusogens of human endogenous retroviral origin in cancer cell fusion will be summarized in this review.

Cell-Cell Fusion Mediated by Viruses and HERV-Derived Fusogens in Cancer Initiation and Progression