Interactions of Ephrins and Eph receptors at cell membranes play crucial role in boundary formation and axon guidance. Extracellular vesicles (EVs), such as exosomes, are formed by cells communicating with each other in paracrine or endocrine manner. Until now, it is thought that direct cell–cell contact is necessary for ephrin and Eph receptor signal transduction. In this review, we discuss recent data that indicate the existence of a novel Eph‐ephrin family anchored exosome signaling pathway in long‐range intercellular communication and provide evidence that this type of signaling elicits cellular responses in cancer cells, independent of juxtacrine interactions. We emphasize that exosome‐anchored Eph/ephrin involves a variety of biological processes and transduction signals, which may serve as a potential diagnostic biomarker.