The causes of metastasis remain unknown, however it has been proposed for nearly a century that metastatic cells are generated by fusion of tumor cells with tumor-associated leukocytes such as macrophages. Indeed, regardless of cell or tissue origin, when cancer cells in the original in situ tumor transform to malignant, invasive cells, they generally become aneuploid and begin to express molecules and traits characteristic of activated macrophages. This includes two key features of malignancy: chemotactic motility and the use of aerobic glycolysis as a metabolic energy source (the Warburg effect). Here we review evidence that these phenomena can be well-explained by macrophage-cancer cell fusion, as evidenced by studies of experimental macrophage-melanoma hybrids generated in vitro and spontaneous host-tumor hybrids in animals and more recently humans. A key finding to emerge is that experimental and spontaneous cancer cell hybrids alike displayed a high degree of constitutive autophagy, a macrophage trait that is expressed under hypoxia and nutrient deprivation as part of the Warburg effect. Subsequent surveys of 21 different human cancers from nearly 2,000 cases recently revealed that the vast majority (~85%) exhibited autophagy and that this was associated with tumor proliferation and metastasis. While much work needs to be done, we posit that these findings with human cancers could be a reflection of widespread leukocyte-cancer cell fusion as an initiator of metastasis. Such fusions would generate hybrids that express the macrophage capabilities for motility and survival under adverse conditions of hypoxia and nutrient deprivation, while at the same time maintaining the deregulated mitotic cycle of the cancer cell fusion partner.