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[Display omitted] • Cytokine release syndrome (CRS) is the major underlying mechanism for multi-organ damage and mortality due to COVID-19. • Interleukin-6 (IL-6) signaling pathway is one of the key mediators of hyperinflammatory syndrome and CRS in COVID-19. • Inhibition of the IL-6 signaling by inhibiting IL-6 receptor (IL-6-R) and Janus-kinase (JAK) can improve the outcome by suppressing the hyperinflammation. • Studies support treatment with tocilizumab and baricitinib to improve the outcome in severely ill COVID-19 patients. • Special clinical considerations, including the timely application of the drug, dosage, the risk of secondary infections must be noticed using IL-6 signaling inhibitors. Since 2019, COVID-19 has become the most important health dilemma around the world. The dysregulated immune response which results in ARDS and cytokine storm has an outstanding role in the progression of pulmonary damage in COVID-19. IL-6, through induction of pro-inflammatory chemokines and cytokines, is the pioneer of the hyperinflammatory condition and cytokine storm in severe COVID-19. Therefore, IL-6 pathway blockade is considered an emerging approach with high efficacy to reduce lung damage in COVID-19. This article aims to review the pleiotropic roles of the IL-6 pathway in lung damage and ARDS in severe COVID-19, and the rationale for IL-6 signaling blockade at different levels, including IL-6 soluble and membrane receptor pathways, IL-6 downstream signaling (such as JAK-STAT) inhibition, and non-specific anti-inflammatory therapeutic approaches. Recent clinical data of each method, with specific concentration on tocilizumab, along with other new drugs, such as sarilumab and siltuximab, have been discussed. Challenges of IL-6 signaling inhibition, such as the risk of superinfection and hepatic injury, and possible solutions have also been explained. Moreover, to achieve the highest efficacy, ongoing clinical trials and special clinical considerations of using different IL-6 inhibitors have been discussed in detail. Special considerations, including the appropriate timing and dosage, monotherapy or combination therapy, and proper side effect managment must be noticed regarding the clinical administration of these drugs. Future studies are still necessary to improve the productivity and unknown aspects of IL-6 signaling blockade for personalized treatment of severe COVID-19. [ABSTRACT FROM AUTHOR]