Idiotypic antigens are clearly defined tumor-associated protein antigens, which can induce protective immunity against lymphoma. Because each patient requires an individual vaccine, idiotypic antigens also provide ideal candidates for exploring the feasibility of replacing protein antigens by DNA vaccines. Component idiotypic variable region genes can be identified in patients' tumor biopsies and rapidly assembled as scFv sequences. These can be used to produce recombinant scFv protein in bacteria, or as direct naked DNA vaccines. A preliminary small trial of DNA vaccines for chemotherapy-resistant patients with lymphoma has begun. Intramuscular idiotypic DNA vaccination in a mouse model induces low levels of anti-idiotypic antibody in serum. Levels can be increased dramatically by coinjection of DNA plasmids encoding either IL-2 or GM-CSF, and specific proliferative anti-idiotypic T cells are induced. However protective immunity remains to be demonstrated, and a possible reason for this may lie in the continued secretion of idiotypic scFv antigen which blocks antibody activity by formation of immune complexes. Methods for regulating secretion of antigen are required before this category of tumor antigen can be fully exploited as a vaccine. The power of DNA technology should allow analysis and manipulation of pathways of antigen presentation to induce maximal therapeutic attack on neoplastic B cells. In addition, lymphoma presents a model for application of DNA technology to the wide range of human tumors known to harbor potential tumor antigens.