Behçet disease (BD) is a multisystem inflammatory disorder of unknown etiology. BD has a multifactorial pathogenesis, and genetics plays a critical role in the development of the disease. Association of HLA-B5/B*51 has been recognized as the strongest genetic susceptibility factor for BD discovered so far. Pathogenic role of HLA-B*51 in BD has yet to be clarified, and available data suggest that there is possibly no single mechanism associated with HLA-B*51. HLA-B*51 may accomplish its effects as a combination of different HLA class I-associated functions and/or structural properties of HLA-B*51 heavy chain. There is no evidence supporting the use of HLA-B*51 as a diagnostic or prognostic marker for BD, and more clinical data must be collected in addition to basic immunological studies to exploit the potential of HLA-B*51 as a biomarker for BD management.