Abstract: Estrogen receptor (ER) are a class of ligand-activated nuclear transcription factor, mediating most of the estrogen signals and play an important role in physiological function in vivo. There are two ER subtypes: ER-α and ER-β. ER-α is mainly expressed in breast and uterine tissues, which has an important role in the development and progression of breast cancer. ER-α36 is a new variant of ER-α, with a molecular weight of 36 kD. It lacks both transactivation domains (activation function 1 and activation function 2) of the classical ER-α. It is predominantly located on the plasma membrane and in the cytoplasm, and modulates nongenomic estrogen signaling. Recent studies found that the dysregulation of ER-α36 is closely associated with carcinogenesis, aggressiveness and therapeutic response of breast cancer, suggesting that ER-α36 may be a novel biomarker of great value for the diagnosis, prognosis, and treatment of breast cancer. In this review, we will overview and update the biological nature and function of ER-α36, and the potential mechanism by which ER-α36 may play an important role in the development of breast cancer resistance to endocrine therapies.