Purpose of Review <p>This review summarizes recent advances in understanding the pathogenesis and therapeutic landscape of juvenile-onset systemic lupus erythematosus (jSLE), with a focus on how emerging genetic and immunologic insights inform patient stratification, targeted treatments, and Treat-to-Target (T2T) approaches in pediatric care.</p> Recent Findings <p>Studies of (ultra-)rare gene variants (e.g., affecting <i>TLR7</i>,<i> UNC93B1</i>,<i> PLD4</i>,<i> PTPN2</i>,<i> BACH2</i>) aided in understanding key pathogenic pathways, and allowed linking these to associated clinical phenotypes. Multi-ancestral genomic studies and cumulative genetic metrics are refining links between patient ancestry, disease expression, genetic burden and variability, supporting personalized management. The therapeutic armamentarium has expanded with the approval of the first two biologic agents for SLE, belimumab and anifrolumab, alongside emerging molecular therapies such as protein kinase inhibitors (including JAK inhibitors), and new approaches to lupus nephritis induction using multitarget regimens that combine standard therapy with belimumab or calcineurin inhibitors. Early experience with CD19-directed CAR-T cells promises remarkable efficacy with sustained drug-free remission and good short-term safety in refractory SLE, although long-term outcomes remain under evaluation. Pediatric T2T strategies have been adapted to jSLE, and achievement of these targets are associate with improved disease control and reduced long-term damage.</p> Summary <p>Recent findings confirm that converging genetic variants and immune pathway dysregulation underlie the heterogeneity of jSLE, supporting precision management. Advances in biologic and cellular therapies, together with paediatric T2T strategies, promise to improve outcomes. Future priorities include integrating genomic stratification into clinical practice and conducting dedicated pediatric trials of novel targeted therapies.</p>