Treating JIA continues to be a challenge. At least half of children with JIA have a more severe polyarticular form that is often refractory to treatment, leading to joint damage, impaired quality of life, disability, and increased healthcare costs. Powerful new biologic medications have improved outcomes, but a recent report from the CARRA Registry indicated that almost half of children with JIA still had active disease despite use of new biologics. The SMART (Trial of Sequential Medications AfteR TNF failure)-JIA trial aims to identify optimal treatment strategies and sequence of medications in children who fail an initial biologic. We aim to strengthen clinical decision-making by identifying biological markers that can predict failure to initial biologic treatment and response to next treatment. The overarching goal is to drive personalized, precision medicine for children with JIA.