Chronic pain is a widespread problem that plagues an estimated 10 to 30% of the world’s population. The current therapeutic repertoire is inadequate in managing patient pain with narcotic use resulting in a drug overdose epidemic, affirming the need for the development of new therapeutics. Adenosine and its four cognate receptors (A1AR, A2AAR, A2BAR, and A3AR) play essential roles in physiological and pathophysiological states, including chronic pain. For decades, preclinical and clinical studies have revealed that adenosine and A1AR-and to a lesser extent A2AAR-selective agonists have analgesic properties, yet their therapeutic utility has been limited by adverse cardiovascular side effects. There is no evidence that A2BAR plays a role in pain. Recent preclinical studies have demonstrated that selective A3AR agonists result in antinociception in models of acute and chronic pain while lacking unwanted side effects. These exciting preclinical observations of A3AR agonists have been bolstered by clinical trials of A3AR agonists in other disease states including rheumatoid arthritis and psoriasis that suggests a clinical benefit without cardiotoxicity. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and examine what is known at present regarding A3AR-mediated antinociception. We will highlight recent findings pertaining to A3AR in pain and describe possible pathways by which A3AR may mediate its effects and the current state of selective A3AR agonists used in pain studies. The adenosine-to-A3AR pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief in patients suffering with chronic pain. © Springer Nature Switzerland AG 2018.