Chimeric antigen receptor T cell (CART) therapy represents a novel and a paradigm-shifting approach to treating cancer. Recent clinical successes have widened the applicability of CD19 CART cells for the treatment of relapsed/refractory B-cell NHL, namely tisagenleclucel and axicabtagene ciloleucel. Tisagenleclucel is also approved for relapsed and/or refractory B-ALL up to age 25. CART therapy is associated with unique and potentially life-threatening toxicities, notably cytokine release syndrome (CRS). A better understanding of the pathogenesis of CRS is crucial to ensure proper management. In this review, CRS definitions, profiles, risk factors and grading systems are discussed. Finally, current and novel investigational approaches and therapies for CRS are summarized.