Estrogen receptors (ERs) are involved in regulating many complex physiological processes in the human body. Abnormal ERs signaling can lead to a variety of diseases, including neurological disorders, osteoporosis, heart disease, and breast cancer. Estrogen receptor α (ERα), estrogen receptor β (ERβ), and the novel G protein-coupled estrogen receptor 1 (GPER-1) are considered to be the most important ERs. ERs knockout models can exhibit disease phenotypes, and can serve as a new animal model for studying ER-related diseases and their interventions.This paper reviews the research progress and important roles of estrogen and ERα, ERβ, and GPER-1, as well as the application of their ER knockout models in diseases.