EphrinB2, a membrane-tethered ligand preferentially binding to its receptor EphB4, is ubiquitously expressed in all mammals. Through the particular bidirectional signaling, EphrinB2 plays a critical role during the development of cardiovascular system, postnatal angiogenesis physiologically and pathologically, and cardiac remodeling after injuries as an emerging role. This review highlights the pivotal involvement of EphrinB2 in heart, from developmental cardiogenesis to pathological cardiac remodeling process. Further potential translational therapies will be discussed in targeting EphrinB2 signaling, to better understand the prevention and treatment of cardiovascular diseases.