Hand, foot and mouth disease (HFMD), which has spread worldwide, is a common childhood infectious disease and a serious threat to children’s health. HFMD is caused by more than 20 enteroviruses, especially enterovirus 71 (EV71). Many studies have shown that HFMD results from the combined effects of virus, host, and environment. After virus invasion, various pathological reactions are caused by escape from surveillance of the host’s natural or acquired immune surveillance. This is not only related to the infection characteristics of the virus, but also to host-related genes such as receptor genes and immune response genes. In recent years, pathogenic host genes related to HFMD have become hot spots for researchers. However, some of the pathogenic related host genes are closely related to regions, races, or populations, and the research conclusion regarding HFMD in different populations in different regions are often not consistent. Therefore, it is necessary to find widely applicable host genes that are closely related to HFMD.Genetic diversity mice are a new tool for simulating population genetic diversity and studying complex traits or diseases. In this paper, we review research on HFMD pathogenicity and related host genes, as well as the advantages of genetic diversity mice in HFMD research.