Summary: Here we review the pathophysiology and management of cytokine release syndrome (CRS) secondary to immunotherapy, and potential options for CRS refractory to IL6 inhibition and glucocorticoids, for which there are no proven treatments. To illustrate, we describe a patient with B-cell acute lymphoblastic leukemia who developed refractory grade 4 CRS following CD19-directed chimeric antigen receptor T-cell therapy, treated with tocilizumab, methylprednisolone, siltuximab, and the IFNγ inhibitor emapalumab, with complete remission from leukemia for 12 months. See related article by Bailey et al., (15).