The spontaneously occurring autoantibodies that are associated with human diseases bear the hallmarks of a typical immune response. The repertoire of autoantibodies is surprisingly limited, however, and is the same in both humans and mice. Neither molecular mimicry nor immune dysregulation accounts for this unexpectedly narrow focus of specificities. Experimental data on the properties of the target autoantigens--such as their structure, catabolism, exposure to the immune system after cell death and recently described immunostimulatory effects on immature dendritic cells--indicate that these properties, in conjunction with the tissue microenvironment, help to select the autoantibody repertoire.