Abstract: Erythropoietin-producing hepatocyte (Eph) receptors are the largest family of the known receptor tyrosine kinases (RTK). The difference between this family and canonical RTKs is that their ligands (Ephrin) are membrane-bound molecules. Hence, Ephrin-Eph-mediated signal transduction relies on direct cell to cell contact. This signaling system plays an important role in regulating embryonic development and maintaining homeostasis under physiological conditions. The dysregulation of Ephrin-Eph signaling system is closely related to carcinogenesis and cancer progression. Studies have shown that among all Eph family members, EphA2 has the closest relationship with tumors. The increased expression of EphA2 can promote the proliferation, survival, migration, invasion, drug resistance, and angiogenesis of breast cancer cells. The increased expression of EphA2 in breast cancer tissues is closely related to poor prognosis in patients. Recently, EphA2 is expected to be a molecular marker for predicting the effect of breast cancer treatment, and thus, can serve as a promising therapeutic target for breast cancer therapy. This review summarized the latest research progress on the contribution of EphA2 in breast cancer therapy resistance.