The natural phenomenon of cell-cell fusion does not only take place in physiological processes, such as placentation, myogenesis, or osteoclastogenesis, but also in pathophysiological processes, such as cancer. More than a century ago postulated, today the hypothesis that the fusion of cancer cells with normal cells leads to the formation of cancer hybrid cells with altered properties is in scientific consensus. Some studies that have investigated the mechanisms and conditions for the fusion of cancer cells with other cells, as well as studies that have characterized the resulting cancer hybrid cells, are presented in this review. Hypoxia and the cytokine TNFα, for example, have been found to promote cell fusion. In addition, it has been found that both the protein Syncytin-1, which normally plays a role in placentation, and phosphatidylserine signaling on the cell membrane are involved in the fusion of cancer cells with other cells. In human cancer, cancer hybrid cells were detected not only in the primary tumor, but also in the circulation of patients as so-called circulating hybrid cells, where they often correlated with a worse outcome. Although some data are available, the questions of how and especially why cancer cells fuse with other cells are still not fully answered.