There is an urgent need for earlier diagnosis of malignancies and more stringent monitoring of relapses after antitumor therapy. In addition, new prognostic markers are needed for risk stratification and design of individualized cancer therapies. New diagnostic and prognostic parameters should overcome the impairments of current standards in a cost-effective manner. Serological approaches measuring spontaneous antibody responses against tumor-associated antigens could be of use as diagnostic and prognostic markers and could also be employed to evaluate response to therapy in cancer patients. Autoantibodies have been suggested to be of frequent and specific occurrence in patients with malignancies and to correlate with clinical parameters. Screening the relevant literature on this topic, we suggest that the analysis of single antibody specificities is unlikely to provide sufficient diagnostic and prognostic accuracy. The combined analysis of autoantibodies targeting different antigens, however, may reach high sensitivity and specificity. In addition, screening cancer patients for autoantibodies might identify subgroups with high relapse risk and a worse prognosis. Larger prospective trials should be initiated to identify sets of tumor-associated autoantibodies suited for the use in diagnostic algorithms for cancer detection and followup.