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Pain, whether it is low back pain, headache, fibromyalgia, etc., is collectively now the #1 clinical problem in the world and, yet, our current imaging methods to correctly identify pain generators remain woefully inaccurate. The lack of unreliable diagnostic tools necessarily facilitates significant misdiagnosis, mismanagement, rampant use of opioids, unhelpful surgeries and, ultimately, therapeutic failures. Relatively recent developments in clinical molecular imaging (MI) are affording the opportunity to pinpoint the exact site(s) of pain generation due to advances in biomarker discovery, imaging technology and radiotracer design. In this presentation, I will show how our group is attempting to develop better approaches to identify pain generators by employing techniques in clinical molecular imaging using PET/MRI. I will describe our efforts to develop a highly specific 18F-labeled positron emission tomography (PET) radiotracers for imaging the sigma-1 receptor (S1R), a master regulator of ion channel activity and molecular biomarker of pain generation. Additionally, we have repurposed 18F-fluordeoxyglucose (FDG) as a marker of inflammation by virtue of its proclivity for metabolically active processes. I will illustrate how this new clinical PET/MR imaging method utilizing the sigma-1 receptor radioligand or FDG is enabling more accurate identification and localization of pain generators and is starting to positively impact the way we treat patients with chronic pain.