SARS-CoV-2 in severely ill patients develop hyperimmune activation leading to cytokine storm occurs and is a potential target for modulation to prevent further lung damage. Therefore, the use of Janus kinase inhibitors (JAKi) targeting IL-6 and other cytokines with JAK-dependent signaling is one way to restrain the excessive level of cytokine signaling.Several clinical trials were initiated to examine the use of baricitinib or other JAK inhibitors such as ruxolitinib and tofacitinib in patients with COVID-19. Despite initial positive findings, there are several JAKi-associated issues to be considered. The reduction of NK cells detected during baricitinib and tofacitinib treatment suggests that use of these drugs in patients with COVID-19 should be limited in its duration. Another possible concern for using JAKi in COVID-19 is the thromboembolic risk associated with this class of drugs. Within the next few months, the clinical approach to treating patients with COVID-19 will guided by the results from ongoing prospective randomized trials and the role for JAKi as well as other small molecules that have the potential to interfere with the cytokine cascade.