The development of random peptide libraries has increased our possibility for analyzing the structural features involved in binding events. Recently, reports have appeared in which these libraries have been successfully used to investigate binding properties of homogeneous proteins such as monoclonal antibodies. However, a more general application of peptide libraries would be the use of polyclonal sera or fluids from patients with autoimmune diseases in biopanning experiments. This would subsequently allow the identification of (auto)antigen leads responsible for the initiation and/or perpetuation of the immune response in these patients. Moreover, the strategy allows the structural characterization of autoantibody specificities in body fluids that have been produced in vivo without the introduction of bias due to preferential B cell growth under in vitro conditions. The application of this novel strategy for selection of antibody ligands for polyclonal sera as well as to study the nature of immune responses to defined proteins will be discussed with emphasis on the development of peptide reagents for diagnostic and vaccine use.