The aberrant release of inflammatory mediators often referred to as a cytokine storm or cytokine release syndrome (CRS), is a common and sometimes fatal complication in acute infectious diseases including Ebola, dengue, COVID-19 and influenza. Fatal CRS occurrences have also plagued the development of highly promising cancer therapies based on T cell engagers and chimeric antigen receptor T cells. CRS is intimately linked with excessive cytokine release resulting in a systemic inflammatory response leading to multiple organ failure. CRS in patients is characterized by high fever, hypotension, hypoxia, and/or multiorgan toxicity. Global immunosuppression or immunosuppressants may control some of these toxicities. However, these therapeutic approaches have demonstrated partial efficacy and can block T cell activation, abrogating clinical benefit which is a concern especially in the context of immunotherapy. Therefore, a better understanding of the mechanisms underpinning the cytokine storm is critically needed and may help in early management of CRS.