Ephrin Type-A receptor 2 (EphA2 receptor, ECK, ARCC2, Epithelial cell kinase) is a transmembrane glycoprotein composed of 976 amino acid residues, with a calculated molecular mass of 130 kDa. It is one member of the largest EPH (erythropoietin-producing hepatoma amplified sequence) family receptor tyrosine kinases. The ligands for the EPH receptors are ephrins, which consist of 9 members that fall into 2 subclasses: the GPI (glycosylphosphatidylinositol) anchored A-class of ligands (Ephrin A1–6) and the transmembrane B-class of ligands (B1–3). Receptor tyrosine kinases of the Eph family and Ephrin ligands play important roles in vascular development, tissue-border formation, cell migration, axon guidance and angiogenesis. EphA2 is largely restricted at low levels on adult proliferating epithelial cells and enriched within sites of cell-cell adhesion in normal epithelial cells. EphA2 expression has been detected in a wide assortment of tissues including the brain, skin, bone marrow, lung, thymus, small intestine, colon, urinary bladder, kidney, liver, spleen, uterus, testis and prostate. EphA2 is also expressed during gastrulation in the ectodermal cells and early embryogenesis in the developing hind brain. EphA2 plays key roles in several developmental processes. Recent studies indicate that EphA2 regulates lens transparency, kidney repair following renal injury, bone remodeling, mammary gland branch morphogenesis, and inner ear development, as well as cell transformation in a variety of tumors. The EphA2 protein was overexpressed in the glioblastoma multiforme (GBM) and anaplastic astrocytoma tissues and was identified as a novel target for the development of glioma vaccines. Recent study demonstrates that expression of EphA2 was correlated with decreased differentiation of hepatocellular carcinoma (HCC), making it a useful molecular marker for HCC progression. Overexpression of EphA2 has been found in a wide array of solid tumors, including breast cancer, prostate cancer, colorectal cancer, ovarian cancer, urinary bladder cancer, non-small cell lung cancer, gastric cancer, squamous cervical carcinoma, esophageal squamous cell carcinoma, and melanoma. Overexpression of EphA2 is significantly associated with cancer progression, metastasis and shorter overall survival in cancers. EphA2 is proposed to be an oncogene and a potential target for cancer therapy.