Human leukocyte antigen (HLA) and transfusion medicine go hand in hand. Transfusion medicine experts are involved in transplants, particularly hematopoietic stem cell transplant. A lot of clinical challenges such as febrile nonhemolytic transfusion reactions, transfusion-related acute lung injury, and also graft versus host disease are caused by HLA antibodies. It is a unique genetic system located on chromosome 6 and its protein products situated on white cells. Histocompatibility in transplant scenario is not the only function of HLA antigens but the main role is to present peptides to immune system and regulate cellular and humoral immunity. HLA Class I (A, B, and C) and HLA Class II (DR, DQ, and DP) antigens are different in structure and function. Typing methods have progressed from earlier serology-based techniques to sequence-based typing to next-generation sequencing. Cross matching techniques have also changed from complement-dependent cytotoxicity (which is still considered a gold standard) to microbead-based assay to flow cytometry. Finally, HLA and its disease association has long been established, particularly so in cases of ankylosing spondylitis.