The cause of metastasis remains elusive despite vast information on cancer cells. We posit that cancer cell fusion with macrophages or other migratory bone marrow-derived cells (BMDCs) provides an explanation. BMDCs fused with tumor cells were present in animal tumor xenografts where they were associated with metastases. In myeloma patients, transcriptionally active myeloma nuclei were incorporated into osteoclasts through fusion. In patients with renal cell carcinoma arising poststem cell transplant, donor genes were incorporated in recipient cancer cell nuclei, most likely through fusion, and showed tumor distribution patterns characteristic of cancer stem cells. Melanoma-macrophage hybrids generated in vitro contained chromosomes from both parental partners, showed increased ploidy, and transcribed and translated genes from both parents. They exhibited chemotactic migration in vitro toward fibronectin and exhibited high frequencies of metastasis when implanted in mice. They produced macromolecules that are characteristic of macrophages and known indicators of metastasis (c-Met, SPARC, MCR1, GnT-V, and the integrin subunits alpha(3), alpha(5), alpha(6), alpha(v), beta(1), beta(3)). They also produced high levels of beta1,6-branched oligosaccharides-predictors of poor survival in patients with melanoma or carcinomas of the breast, lung, and colon. We thus hypothesize that such gene expression patterns in cancer are generated through fusion. Tumor hybrids also showed active autophagy, a characteristic of both metastatic cancers and macrophages. BMDC-tumor cell fusion explains epidermal-mesenchymal transition in cancer since BMDCs express mesodermal traits and epithelial-mesenchymal transition regulators (Twist, SPARC, and others). If BMDC-tumor cell fusion underlies invasion and metastasis in human cancer, new approaches for therapeutic intervention would be mandated.