A significant portion of the world’s population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) Over half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A*24, HLA-B*27, HLA-B*53 and HLA-B*58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B*44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy.