It is nearly 20 years since the first reports appeared linking genes within the human major histocompatibility complex, the HLA region, with disease. The literature now contains many hundreds of papers confirming an increased frequency of different HLA antigens in a diverse spectrum of conditions, ranging from narcolepsy to diabetes. Over the years many different hypotheses have been proposed to explain this association, but none has been proven. Nevertheless, our knowledge of the HLA region and the function of its many genes is expanding rapidly and the pathogenesis of many HLA-linked diseases may soon become apparent. In this review we aim to provide clinicians with a broad understanding of the basis for the association between HLA and disease. We will describe the genes of the HLA region before discussing the diseases with which they are linked. Finally, we will explore mechanisms through which HLA genes might influence disease.