Eph/ephrin signaling plays important roles both in embryonic development and human disease. The Eph receptors are involved in tumor development, progression, metastasis, and prognosis. The tumor microenvironment plays a critical role in tumor initiation, progression, metastasis, and resistance to therapy. Increasing data show that Ephs and ephrins mediate cell-cell interactions both in tumor cells and in tumor microenvironment. This review focuses on recent advances in dissecting the role of Eph and ephrin in tumor cells, tumor angiogenesis, epithelial-mesenchymal transition, hypoxia, and inflammation.