The use of cell fusion has been applied to the development of immunotherapy cancer vaccines. This has typically involved the fusion of dendritic cells and tumor cells. The resultant hybrid uses the specialized antigen presentation properties supplied by the dendritic cell fusion partner to present tumor antigens, both known and yet undefined, to the immune system. This chapter critically examines the scientific foundation of this approach mainly focusing on studies over the last decade. This will include basic principles of tumor fusion vaccines, summary of pre-clinical and clinical data, concluding with remaining challenges and directions.