An unusual form of lung disease has begun to affect some children with systemic juvenile idiopathic arthritis (JIA), coincident with increasing utilization of interleukin‐1 (IL‐1) and IL‐6 antagonists. Many children with systemic JIA–associated lung disease (SJIA‐LD) have a history of clinical and laboratory features resembling drug reaction with eosinophilia and systemic symptoms (DRESS), a presentation now convincingly associated with HLA–DRB1*15. Treatment of DRESS typically requires drug discontinuation, a daunting prospect for clinicians and families who rely upon these agents. Here we review SJIA‐LD and its associated DRESS‐like phenotype. We suggest an alternative explanation, the cytokine plasticity hypothesis, proposing that IL‐1 and IL‐6 blockers modulate the milieu in which T cells develop, leading to a pathologic immune response triggered through exposure to common microbes, or to other exogenous or endogenous antigens, rather than to the drugs themselves. This hypothesis differs from DRESS in mechanism but also in clinical implications, predicting that control of pathogenic T cells could permit continued use of IL‐1 and IL‐6 antagonists in some individuals. The spectrum posed by these two hypotheses provides a conceptual framework that will guide investigation into the pathogenesis of SJIA‐LD and may open up new therapeutic avenues for patients with systemic JIA.