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Chronic pain remains one of the leading drivers of disability worldwide, yet the clinical reality is sobering: across nearly all treatments, average benefits are modest, and individual responses are highly variable.1 Part of this gap is definitional and biological: pain can reflect differing relative contributions of peripheral nociceptive drive, central neuroplasticity, and cognitive–affective processes. This is even more relevant in pain conditions without a clearly defined dominant pathophysiological mechanism, where treatment selection is often less targeted and intervention failure is more common. The practical result is that “the average patient” can be a misleading abstraction when underlying pain mechanisms and treatment responses diverge at the individual level. Rather than choosing between mechanistic science and clinical pragmatism, the moment demands parallel progress: advancing mechanism-informed models of pain while simultaneously sharpening clinical decision-making to identify who benefits, who does not, and understanding why. Refining patient selection by identifying mechanisms associated with a lower likelihood of response to anatomically-targeted interventions such as surgery and injections has the potential to improve risk-benefit and cost-effectiveness ratios, which are critical in an era defined by reductions in access to care.