The identification of novel cell surface antigens present on tumor cells is crucial for developing new cancer therapies. Intact, viable cancer cells, which display cancer-restricted antigens in their native conformation and cellular context, provide a rich source of novel antigens. Antibody-based technologies are being used to probe the surface of intact cancer cells for cancer-specific antigen targets. In addition to identifying new proteins, these approaches are generating monoclonal antibodies (MAbs) to cancer-specific epitopes and nonprotein targets not amenable to genomics-based approaches. The multiple cell-based approaches developing epitope-specific MAbs to cancer antigens is likely to usher in a new era of therapeutic MAb target discovery.