The major histocompatibility complex (MHC) was initially defined as the genetic locus encoding the Class I and Class II highly polymorphic cell surface antigens that are now known to present antigen to matched sets of T cell receptors. Genes for several diverse complement components, specifically Bf, C2, and C4 were found between the Class I and II genes, in a region later dubbed Class III. More recently, several genes have been described that are encoded in the telomeric end of the Class III region and that appear to be involved in both global and specific inflammatory responses. Due to this commonality of function this gene-rich region was dubbed Class IV, and includes the TNF family, AIF1, and HSP70. The genes of the Class III and Class IV regions are sufficiently divergent in sequence and structure so that clustering is not explicable in terms of gene duplication or divergence. We present some of the newer pertinent information and puzzling features of the genes embraced in the Class IV region and discuss possible roles in specific autoimmune diseases linked to this region.