Systemic-onset juvenile idiopathic arthritis (SoJIA) accounts for a relatively small proportion of patients with juvenile arthritis. Its clinical manifestations are unique among the subsets of JIA and studies of cytokine profiles suggest differences between the underlying mechanisms of the different diseases. SoJIA may, in fact, be better classified separately from other subtypes of JIA. New biologic agents that are currently licensed or being tested, target the cytokines interleukin-1 and interleukin-6 and appear to be effective in treating SoJIA. By contrast, anti-tumor necrosis factor therapy is much less, if at all, successful in this subgroup of JIA. This article reviews the current literature on the pathogenesis and treatment of SoJIA.