The major histocompatibility complex (MHC) is closely related to immune regulation. MHC shows distinct genetic polymorphism, and there are also species differences in MHC restriction. The human MHC is called human leukocyte antigen (HLA), and the mouse MHC is called H-2. The construction of humanized MHC transgenic mouse models is an important strategy to overcome the differences in MHC among species and simulate the characteristics of a 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. The development of HLA Ⅰ transgenic mouse model went through three stages, at present, the strategy of knocking out H-2K b and H-2D b or murine β2m is adopted to eliminate the competitive inhibition of HLA Ⅰ molecules by endogenous H-2 class Ⅰ molecules. In the construction of an HLA Ⅱ transgenic mouse model, the β strand of murine origin is knocked out and HLA Ⅱ class genes are inserted. With the optimization of construction strategies, MHC transgenic mouse models have been applied to epitope vaccine development,tumor treatment, and genetic disease-association studies, becoming a powerful tool for preclinical trials. In this paper, we summarize the relevant data on MHC transgenic mouse models, as well as the construction strategies used for MHC transgenic mouse models and their application in vaccine development and disease treatment.