Many autoimmune diseases are characterized by autoantibody subsets that are associated with specific clinical manifestations. The primary genetic associations of these autoantibodies are with MHC genes, most specifically HLA class II, which in many instances better explain the HLA association of the disease per se. It is noteworthy that certain genes and haplotypes, notably HLA-DRB1*0301, DQA1*0501, DQB1*0201 in Caucasians and DRB1*0405, DQA1*03, DQB1*0401 in Asians, as well as PTPN22, seem to be associated with a variety of autoimmune diseases. On the other hand, others are more disease specific (HLA-DRB1*11 for systemic sclerosis and HLA-DRB1 alleles encoding the "shared epitope" in RA) as well as non MHC genes, such as FcyRIIa and IIIa in SLE, the beta2 glycoprotein I gene in the aPL syndrome, and the TSHR gene in Graves' disease). Autoantibody responses also are influenced by the presence of specific MHC and non-MHC genes which may not be associated with the disease per se. These novel associations offer new clues not only to pathogenesis but also to potential therapeutic targets.