Extracellular vesicles (EVs) are nanosized particles that have emerged as mediators for intercellular communication in physiologic and pathologic conditions. EVs carry signaling information on their bilipid membrane as well as cargo within, allowing them to perform a wide range of biologic processes and contribute to pathophysiologic roles in a wide range of diseases, including cancer, autoimmune diseases and coagulopathy. This review will specifically address the function of surface molecules on EVs under normal and diseased conditions, as well as their potential to emerge as therapeutic targets in clinical settings, and the importance of further research on the surface topography of EVs.