Pain is a complex common health problem, with important implications for quality of life and with huge economic consequences. Pain can be elicited due to tissue damage, as well as other multiple factors such as inflammation and oxidative stress. Can there be one therapeutic pathway which may target multiple etiologic factors in pain? In the present article, we review evidence for the relationships between vagal nerve activity and pain, and between vagal nerve activity and five factors which are etiologic to or protective in pain. Specifically, vagal nerve activity inhibits inflammation, oxidative stress and sympathetic activity, activates brain regions that can oppose the brain «pain matrix», and finally it might influence the analgesic effects of opioids. Together, these can explain the anti-nociceptive effects of vagal nerve activation or of acetylcholine, the principal vagal nerve neurotransmitter. These findings form an evidence-based neurobiological rationale for testing and possibly implementing different vagal nerve activating treatments in pain conditions. Perspective: In this article, we show evidence for the relationships between vagal nerve activity and pain, and between vagal nerve activity and five factors which are etiologic to pain. Given the evidence and effects of the vagus nerve activation in pain, people involved in pain therapy may need to seriously consider activation of this nerve.