Human leukocyte antigen (HLA) class I molecules are involved in the presentation of antigenic peptides to CD8(+) cytotoxic T lymphocytes (CTLs), which is important for the development of cellular immunity during viral infections and in cancers. HLA-A2 is one of the most frequent HLA class I specificities and thus is extensively studied structurally and functionally. Since its discovery, more than 300 allelic variants of this HLA specificity have been recorded. Among the HLA-A2 allelic variants, HLA-A*02:01 is the most prevalent, hence commonly used as a model to study HLA-A2-restricted CTL responses. However, HLA-A2 alleles are unevenly distributed globally such that HLA-A2 allelic variants besides A*02:01 are expressed at considerably high frequencies in Asian and African populations. Furthermore, increasing evidence of variations in the peptide-binding repertoire and CTL responses among HLA-A2 allelic variants suggests the need to understand these differences among various frequently expressed HLA-A2 molecules. In this review, the structural and functional distinctiveness of HLA-A2 allelic variants will be discussed.