The expansion and dissemination of interventional cryoneurolysis in recent years has been fueled by the integration of advanced imaging guidance, the evolution of our understanding of neuropathologic processes after exposure of nerves to cold, and opportunities for its use beyond pain management. The clinical translation of cryoneurolysis through interventional radiology requires consideration of many factors, including (a) the supply and composition of target nerves, (b) the value of diagnostic injection with imaging guidance for confirmation, (c) the integration of advanced imaging guidance that allows safe ablation, (d) the difference between neoplastic and nonneoplastic causes of pain, (e) the phenomenon of percutaneously induced neuroregeneration, (f) the potential to manage conditions other than pain, (g) the consideration of protocols, (h) the limitations of current technology, and (i) the potential complications and adverse effects. Cryoneurolysis has societal and legislative endorsement as an effective nonopioid option for pain palliation. The Centers for Medicare and Medicaid Services (CMS) approved three new category III Current Procedural Terminology (CPT) codes specifically for the cryoablation of nerves with advanced imaging guidance. Interventional radiologists who are aware of nerve-directed strategies see eligible patients in their daily practice and have opportunities to bundle procedures (eg, celiac plexus block at the time of a biliary drain for pancreatic cancer with low bile duct obstruction), offering an avenue to serve the patient, reduce opioid dependence, allow faster discharge, and establish name recognition of interventional radiologists. Also, the ability to use CT to target deep structures accurately and swiftly, often with only local anesthesia, compared with the usual monitored anesthesia care in a surgical setting, may provide another avenue to build a cryoneurolysis practice. ©RSNA, 2022.