Study Design Single case report with repeated measures over 18 months. Background Management of persistent low back pain (PLBP) associated with high pain-related fear is complex. This case report aims to provide clinicians with insight into the process of change in a person with PLBP and high bending-related fear, who was managed with an individualized behavioral approach of cognitive functional therapy. Case Description A retired manual worker with PLBP believed that his spine was degenerating, that bending would hurt him, and that avoidance was the only form of pain control. At baseline, he presented high levels of pain-related fear on the Tampa Scale of Kinesiophobia (score, 47/68) and a high-risk profile on the Örebro Musculoskeletal Pain Questionnaire (score, 61/100). Unhelpful beliefs and behaviors led to a vicious cycle of fear and disengagement from valued life activities. Guided behavioral experiments were used to challenge his thoughts and protective responses, indicating that his behavior was modifiable and the pain controllable. Using a multidimensional clinical-reasoning framework, cognitive functional therapy management was tailored to target key drivers of PLBP and delivered over 6 sessions in a 3-month period. Outcomes Over an 18-month clinical journey, he demonstrated improvements in bending-related fear, pain expectancy, and pain experience, and substantial changes in pain-related fear (Tampa Scale of Kinesiophobia: 33/68; change, -14 points) and risk profile (Örebro Musculoskeletal Pain Questionnaire: 36/100; change, -25 points). Clinical interviews at 6 and 18 months revealed positive changes in mindset, understanding of pain, perceived pain control, and behavioral responses to pain. Discussion This case report provides clinicians with an insight to using a multidimensional clinical-reasoning framework to identify and target the key drivers of the disorder, and to using cognitive functional therapy to address unhelpful psychological and behavioral responses to pain in a person with PLBP and high pain-related fear. Level of Evidence Therapy, level 5. J Orthop Sports Phys Ther 2017;47(9):637-651. Epub 13 Jul 2017. doi:10.2519/jospt.2017.7371.