Systemic juvenile idiopathic arthritis (sJIA) is a severe disorder now linked more to autoinflammation than to autoimmunity. Clinical and laboratory evidence support the pathogenetic role of interleukin-1 (IL-1), and blockade of this cytokine has proved to be very effective in the treatment of sJIA. There are now several agents that block IL-1 available on the market. This article reviews the efficacy and safety of these drugs for the treatment of sJIA on the basis of published data, and offers the current view on treating sJIA according to its different phenotypes. There are no head to head trials among the different IL-1 inhibitors, and although efficacy has been demonstrated for all of them, it is still unknown which one would be more appropriate for which particular situation. The presence of synovitis in addition to active systemic features might be relevant for these choices. In addition, complications such as macrophage activation syndrome can be important since, on one hand, it has been associated with biologic therapy administration and, on another, there have been some reports of this complication being treated with anti-IL-1. Current recommendations by the American College of Rheumatology are now outdated, and new ones are being prepared. In the meantime, basic and clinical research is advancing in order to identify new treatment targets and to evaluate the different protocols currently in use.