Background Ephs is the largest subfamily of receptor tyrosine kinases(RTKs) in the human genome, which binds to the ligand, Ephrins, to regulate many development processes, including tissue-border formation, re-angiogenesis, axon guidance, and synaptic plasticity. Recent studies indicate that EphrinBs/EphBs signaling regulates the nociceptive process. Objective Here we retrospectively summarized the mechanism of EphrinBs/EphBs signaling pathway in regulating the process of pain. Content A great deal of studies have shown that EphrinBs/EphBs signaling pathway modulates the development of nociceptive process through upregulating the excitability of nociceptive dorsal root ganglia and wide dynamic range neurons in spinal dorsal horn, producing central sensitization, and activating the downstream mitogen-activated protein kinase （MAPKs） pathway. Trend Clarifying the downstream mechanism of EphrinBs/EphBs signaling pathway in the nociceptive process will be helpful helpful to find a new potential target for the treatment of pain.