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Chimeric antigen receptor (CAR)-modified T cells and bispecific T cell–engaging antibodies have demonstrated dramatic clinical responses in recent clinical trials. The hallmark of these novel highly active immunotherapies is nonphysiologic T cell activation, which has correlated not only with greatly increased efficacy but also with notable toxicity in some cases. We and others have observed a cytokine release syndrome (CRS), which correlates with both toxicity and efficacy in patients receiving T cell–engaging therapies. In addition to elevations in effector cytokines, such as interferon-γ, cytokines associated with hemophagocytic lymphohistiocytosis or macrophage activation syndrome, such as interleukin (IL)-10 and IL-6, may also be markedly elevated. Whereas corticosteroids may control some of these toxicities, their potential to block T cell activation and abrogate clinical benefit is a concern. Detailed studies of T cell proliferation and the resultant immune activation produced by these novel therapies have led to more targeted approaches that have the potential to provide superior toxicity control without compromising efficacy. One approach we have developed targets IL-6, a prominent cytokine in CRS, using the IL-6R antagonist tocilizumab. We will review the pathophysiology and management options for CRS associated with T cell–engaging therapies.