In recent years, a number of single-pot antibody (Ab) libraries have been described, which permit the rapid isolation of high-affinity Abs against large panels of antigens (Ags). Naïve libraries have been generated by tapping the natural primary (unselected) immune repertoire via cloning of Abs that recognize a variety of Ags (1,2). The rearranged V genes were amplified with the polymerase chain reaction (PCR) from B-cell mRNAs encoding immunoglobulin M (IgM) taken from nonimmunized donors. By using this procedure, Abs were recovered prior to encounter with Ag and unscreened for tolerance by the immune system. Indeed, a naïve library represents a good source of Abs against self, nonimmunogenic, and toxic Ags if the library is sufficiently large and diverse.