The characterization and clinical assessment of the human leukocyte antigen (HLA) genes has undergone significant advances over the last 50 years. As serological methods have given way to more-advanced molecular methods, our understanding of the complexity and polymorphic nature of the HLA genes has been substantially improved. From its basis in serological and cellular testing in the 1960s (antibody and mixed lymphocyte culture) (1–5), through two-dimensional electrophoresis and restriction fragment length polymorphism analysis in the 1970s and '80s (5, 6), the development of PCR in the mid-1980s revolutionized our molecular understanding of the HLA genes. From PCR, methods utilizing sequence-specific oligonucleotide probes (SSOs) and sequence-specific primers (SSPs) provided the means for more directly evaluating the highly variable sequence motifs within the HLA genes (7–10). Subsequently, in the 1990s, Sanger sequence-based typing (SBT) significantly advanced tissue typing and transplantation genetics (11–14) by providing an unprecedented molecular view of HLA polymorphism in the context of exonic variation. Most recently, next-generation sequencing (NGS) appears to definitively address HLA typing complexity, as it provides entire HLA gene characterization and haploid sequence determination.