Population studies reveal HLA class I and class II gene polymorphisms associated with all the common chronic autoimmune diseases, notably spondylarthropathies, rheumatoid arthritis, multiple sclerosis and type I diabetes. We here discuss the exceptionally high levels of nucleotide diversity in the MHC region likely to reflect not only balancing selection acting on the epitope binding sites but also natural selection operating on the promoter region. The latter possibility is supported by functional studies with promoters, higher levels of diversity in the promoters of class II than class I genes and the relatively high frequency of single nucleotide polymorphisms around transcription factor binding sites. This, we argue, reflects the need for an appropriate level of signalling at the immunological synapse. We here summarise our knowledge of HLA promoter polymorphisms and how these translate into differential expression, T cell polarisation and inflammation. We discuss current strategies for pharmaceutical intervention in HLA expression.