The presence of circulating islet cell autoantibodies distinguishes type 1A diabetes (T1D) from other diabetic syndromes and determination of autoantigen genes and proteins is instrumental in understanding T1D as a clinical entity and in investigating the pathogenesis of the disease. ZnT8 was recently defined as a candidate autoantigen based on a -bioinformatics analysis focused on discovery of beta-cell-specific proteins associated with the regulatory pathway of secretion. The native molecule does not lend itself easily to solution-phase autoantibody assays, but ligands based on the predicted domain structure and molecular modeling have led to robust diagnostic procedures showing high specificities and sensitivities that complement current T1D autoantibody assays and add to the predictive value of their measurement. The incorporation of genetic and structural epitope analysis into ZnT8A determinations adds a further dimension to its diagnostic value and understanding of its role in the autoimmune disease process.