Among subcategories of juvenile idiopathic arthritis (JIA), one stands out as very different from the others. Systemic JIA involves an abrupt onset of fever and in most cases an evanescent erythematous rash, sometimes preceding the appearance of overt synovitis by weeks or months. While some patients continue this so-called systemic phase for years, a more common course is for fevers and rash to fade away, leaving behind a chronic, destructive, and often therapy-resistant arthritis. Recent data have raised the possibility that early cytokine blockage might abrogate this latter phase, reflecting a potential “window of opportunity” in the care of these challenging patients. The purpose of this review is to evaluate the data in support of, and against, this hypothesis, and more broadly to consider how human and murine immunologic studies could help us understand the transition from systemic phase to chronic persistent arthritis in systemic JIA.