Systemic juvenile idiopathic arthritis (s-JIA) is clinically distinct from other types of JIA. It is typified by extraarticular features such as quotidian fevers, rash, splenomegaly, lymphadenopathy, laboratory abnormalities (including leukocytosis, thrombocytosis, anemia, hyperferritinemia, and elevated inflammatory markers), and a close association with the macrophage activation syndrome. Recent investigations have highlighted dysregulation of the innate immune system as the critical pathogenic driver of s-JIA. Key innate immune mediators of s-JIA are the macrophage-derived cytokines interleukin-1 (IL-1) and IL-6. Increased understanding of the roles of IL-1 and IL-6 in the pathogenesis of s-JIA has led to major changes in therapeutic options. Until recently, the most commonly used medications included corticosteroids, methotrexate, and tumor necrosis factor (TNF) inhibitors, which are incompletely effective in most cases. Newer biologic agents targeting IL-1 and IL-6 have proven very effective in treating s-JIA and in minimizing corticosteroid exposure. Here we review recent advances in the understanding of the pathogenesis of s-JIA and the recent clinical trials that have revolutionized the care of children with s-JIA.