Pain remains a major clinical challenge because there are no effective analgesics for some pain conditions and the mainstay analgesics for severe pain, opioids, have serious unwanted effects. There is a dire need for novel analgesics in the clinic. Imidazoline receptors are a family of three receptors (I₁, I₂ and I₃) that all can recognize compounds with an imidazoline structure. Accumulating evidence suggests that I₂ receptors are involved in pain modulation. Ligands acting at I₂ receptors are effective for tonic inflammatory and neuropathic pain but are much less effective for acute phasic pain. When studied in combination, I₂ receptor ligands enhance the analgesic effects of opioids in both acute phasic and chronic tonic pain. During chronic use, patients can develop tolerance to and dependence on opioids. Imidazoline I₂ receptor ligands can attenuate the development of tolerance to opioid analgesia and inhibit drug withdrawal or antagonist precipitation induced abstinence syndrome in animals. Taken together, drugs acting on I₂ receptors may be useful as a monotherapy or combined with opioids as an adjuvant for treating pain. Future studies should focus on understanding the relative efficacy of I₂ receptor ligands and developing new compounds to fill the gap in intrinsic efficacy continuum of I₂ receptors.