Fusions of dendritic cells (DC) and tumor cells are increasingly used in tumor immunotherapy. The strategy for DC-tumor fusion vaccine is based on the fact that DC are the most potent antigen-presenting cells in the body, whereas tumor cells express abundant tumor antigens. The fusion of these two cell types creates a heterokaryon with both DCderived costimulatory molecules, efficient antigen- processing and -presentation machinery, and tumor-derived antigens. In animal and human studies, DC-tumor fusion cells (FC) have been shown to possess the elements essential for processing and presenting tumor antigens to host immune cells and for inducing effective immune response that is able to break T-cell tolerance to tumor-associated antigens; moreover, they have been demonstrated to provide protection against challenge with tumor cells and to regress established tumors. Despite these unique features of DC-tumor fusion cells and the observation of tumor eradication in animal studies, only limited, yet encouraging, success has been seen in clinical trials. This article reviews the methods used for the preparation and selection of DC-tumor fusion cells and analyzes the factors influencing the success or failure of FC-mediated immunotherapy. In addition, it discusses the challenges facing FC vaccine, including preparation, selection, and quality control of DC-tumor fusion cells, and approaches for enhancing antitumor immunity.