The screening of tumor-derived expression libraries for antigens detected by high-titer immunoglobulin G antibodies from the sera of patients with cancer by SEREX (serological identification of antigens by recombinant expression cloning) allows a systematic search for antigens of human cancers. SEREX has led to the identification of a multitude of new tumor antigens in many different tumor entities. According to their specificities, the antigens can be grouped into different classes, of which the cancer testis antigens appear to be the most attractive candidates for vaccine development. Serologically defined human tumor antigens facilitate the identification of antigenic peptides recognized by tumor-specific T lymphocytes, thus providing a molecular basis for polyvalent peptide-based and gene-therapeutic vaccine strategies in a wide variety of human neoplasms. Moreover, many of the SEREX-identified antigens seem to play a functional role in the pathogenesis of malignant disease. With more than 2000 antigens listed in the SEREX database, it appears that tumor antigens that have resisted discovery to date are expressed in only a small minority of tumors, thus limiting their clinical usefulness. Novel strategies are necessary to identify antigens that can serve as a vaccine target in a broad spectrum of non-Hodgkin's lymphoma patients.