The increased incidence of autoantibodies in malignancies has been described since the 1970s. Thus the ability to determine molecular fingerprinting of autoantibodies (antibody signatures) may provide useful clinical diagnostic and prognostic information. This review describes the use of several proteomic approaches for the identification of antigens recognized by these autoantibodies. Serological proteome analysis (SERPA) associates separation of tumor cell proteins on 2-DE gels, western blotting with sera of patients and healthy subjects, and identification of the detected antigens by MS. Alternatively, Multiple Affinity Protein Profiling (MAPPing) combines isolation of the antigens recognized by patient antibodies by 2-D immunoaffinity chromatography, and identification by MS/MS. The use and limitations of reverse phase protein microarrays for testing patient serum containing autoantibodies are also considered. Lastly, the most important difficulty of any proteomically identified autoantibody signature is validation in patient cohorts or clinical samples.