Here we report the first complete sequence and gene map of a human major histocompatibility complex (MHC), a region on chromosome 6 which is essential to the immune system. When it was discovered over 50 years ago the region was thought to specify histocompatibility genes, but their nature has been resolved only in the last two decades. Although many of the 224 identified gene loci (128 predicted to be expressed) are still of unknown function, we estimate that about 40% of the expressed genes have immune system function. Over 50% of the MHC has been sequenced twice, in different haplotypes, giving insight into the extraordinary polymorphism and evolution of this region. Several genes, particularly of the MHC class II and III regions, can be traced by sequence similarity and synteny to over 700 million years ago, clearly predating the emergence of the adaptive immune system some 400 million years ago. The sequence is expected to be invaluable for the identification of many common disease loci. In the past, the search for these loci has been hampered by the complexity of high gene density and linkage disequilibrium.