Erythropoietin-producing hepatocellular A2 (EphA2) is a member of the Eph tyrosine kinase receptor family that has been linked to various biological processes. In tumors, EphA2 overexpression is associated with noncanonical pathway activation, tumor progression, and a poor prognosis, which has emphasized its importance as a marker of malignancy. Studies on numerous cancer models have highlighted EphA2's dual and often contradictory action, which can be attributed to EphA2's interactions involving multiple pathways and different ligands, as well as the heterogeneity of the tumor microenvironment. In this review, we summarize the main mechanisms underlying EphA2 dysregulation in cancer, highlighting its molecular complexity. Then, we analyze therapies that have been developed over time to counteract its action. We discuss the limitations of the described approaches, emphasizing the fact that the goal of new options is high specificity without losing therapeutic efficacy. For this reason, immunotherapy or the emerging field of targeted protein degradation with proteolysis-targeting chimeras (PROTACs) may represent a promising solution that can be developed based on a deeper understanding of the molecular mechanisms sustaining EphA2 oncogenic activity.