Behçet's disease (BD) is a complex inflammatory disease, of unknown etiology. While disease pathogenesis remains unclear, a strong relationship between BD and HLA-B51 has been established over the last 30 years. A number of theories exist regarding the cause of BD; however, few are able to account for the increased rates of HLA-B51 positive individuals, particularly around the Mediterranean basin and Middle-East where the prevalence is highest. This review outlines current immunogenetic data on BD and the immunoregulatory role natural killer cells may play. It also describes the interaction of the killer immunoglobulin-like receptor - KIR3DL1 with its ligand Bw4, which is found on HLA-B51. Finally, CD94/NKG2D, MICA, and ERAP are outlined with regard to their potential roles in BD.