Even though the merger of two (or more) cells appears simple, the whole process is rather complex and not yet fully understood. While it is clear that cell–cell fusion and virus–cell fusion depends on the expression and presence of specific fusion-relevant proteins and molecules, such as fusogens in general and their receptors, cell–cell adhesion molecules, proteases, and phospholipids like phosphatidylserine (PS), the underlying mechanisms that regulate and control cell–cell fusion still remains to be elucidated. In this regard, it is necessary to discriminate between physiological and pathophysiological cell–cell fusion processes. In physiological cell–cell merger, the fusion machinery, which is composed of all fusion-relevant proteins and molecules, is initiated in individual cells in an inherent and even evolutionarily conserved time- and development-dependent manner. The sperm and the oocyte have to fuse during fertilization, the merger of trophoblasts into multinucleated syncytiotrophoblasts is important for proper placenta formation and function, and multinucleated myofibers cannot originate without the fusion of single-nucleated myoblasts. In contrast, cell–cell fusion events that occur in adult organisms in a rather non-evolutionarily conserved manner, such as the merger of cells in tissue regeneration processes or in tumor tissues, remain ambiguous. While it is clear that the fusion machinery must be active, it is not completely understood how the merger machinery is ultimately initiated and controlled in these cells, which particularly applies to tumor cells. In fact, it is well-known that tumor cells can fuse with other normal cells, such as macrophages, fibroblasts, and stem cells, but it is completely unclear why tumor cells and normal cells do this. Is this the reactivation of probably evolutionarily conserved mechanisms that have occurred in cancer cells and normal cells, or is this purely random? And if so, does the merging of cancer cells and normal cells have any benefits for the organism, for example, by enabling the immune system to better recognize and eliminate the fused tumor cells? Or, on the other hand, does illicit tumor cell fusion compound tumor growth and evolution via genomic rewiring/reprogramming and the inheritance of genomic instability to the next generation? Thus, the aim of this book is to bring more light into the complex, tightly regulated, and fascinating process of cell–cell fusion.