As the immunobiological function of the HLA (human leucocyte antigen) class I and II molecules was revealed, we have seen an explosive development of the HLA field. Today, the HLA complex occupies a central position in basic and clinical immunology. In this Opinion article, I will briefly discuss some challenges which in my opinion are more important than others in the near future of HLA, with a focus on products of the classical HLA class I and II genes. Matching for HLA antigens will continue to be of importance in organ and hematopoietic stem cell transplantations. In the latter field, induction of graft-versus-leukemia effects will receive greater attention, where HLA will play a central role. It is anticipated that we will see an extensive development in our knowledge of the etiology and pathogenesis of autoimmune diseases, where some HLA class I and II genes by far are the strongest predisposing genes. To predict and prevent autoimmune diseases will be a major challenge for the HLA field in the future. HLA will also be of increasing importance in pharmacogenomics, vaccinations and anthropology. Together, this will leave the HLA field with many new challenges and opportunities, which in the future will require more focus on functional aspects of the immunogenetics of HLA.