The major histocompatibility complex (MHC) is closely related to immune regulation, and not only has genetic polymorphisms, but also has species differences in MHC restriction. The construction of humanized MHC transgenic mouse models is an important strategy to break through the differences of MHC species and simulate the characteristics of human immune response. MHC transgenic mice are mainly divided into MHC I or MHC II. single transgenic mouse models and MHC I and MHC II double transgenic mouse models. At present, the strategy of knocking out H-2Kb and H-2Db or knocking out murine β2m is adopted to eliminate the competitive inhibition of HLA I molecules by endogenous H-2 class I molecules, and the construction of HLA II transgenic mouse model is to knock out the β strand of murine origin and transfer it to HLA II. class genes.With the optimization of construction strategies, MHC transgenic mouse models have been applied to epitope vaccine development, tumor treatment, and disease genetic association studies, becoming a powerful tool for preclinical trials. In this paper, we summarize the relevant data of MHC transgenic mouse models, and summarize the construction strategies of MHC transgenic mouse models and their application progress in vaccine development and disease treatment.