Eph receptors comprise the largest family of receptor tyrosine kinases (RTKs), with fourteen receptors divided into two subfamilies — EphAs and EphBs. Yet, despite their multitude of functions in almost all tissues of the body, these receptors represent one of the most underappreciated RTK families. What makes Eph receptors unique is that their cognate ligands, the ephrins, are tethered to the cell surface, in contrast to other RTKs whose ligands are generally soluble. This phenomenon means that signalling through Eph receptors is largely dependent on cell–cell contact. In this way, Eph receptors allow cells to sense their immediate surrounding cellular microenvironment and make appropriate behavioural decisions. For example, Eph receptors control whether two contacting cells are repelled by, or attracted to, each other. As such, they play an important role in normal physiological processes, including embryonic tissue boundary formation and directional guidance of developing axons, while in adult tissues they aid in wound healing and the maintenance of intestinal cell populations in particular compartments. Aberrant expression of these receptors, however, has been implicated in many pathologies, including cancer and neurodegenerative diseases. In this Primer we will discuss some of the key aspects of signalling by Ephs and ephrins that make them pivotal players in health and disease.