The burden of disease caused by the new SARS-CoV-2 coronavirus is focused on adults. In children, this infection manifests as a mild and even asymptomatic acute respiratory illness. Reports in April 2020 described a multisystem inflammatory syndrome in children (MIS-C) occurring 2 to 6 weeks after SARS-CoV-2 wave peak. Clinical manifestations included fever, gastrointestinal symptoms, Kawasaki Disease criteria, hypercoagulability, and laboratory parameters within severe inflammatory range. There is no certainty of the pathophysiology of this syndrome. It is thought to be driven by a post-viral dysregulated immune response. The disease can be life threatening, frequently presented as rapid-onset severe organ failure and need for pediatric critical care support. Cardiovascular dysfunction and coronary involvement are the most serious complications. The clinical and laboratory features of MIS-C indicate that the inflammation is exceptionally high; thus, empirical immunomodulation is the current therapy, leading to good clinical results. Once vaccination against SARS-CoV-2 began, a drop in the incidence of MIS-C happened. In the post-COVID era, permanent vaccination of the population in countries that are already vaccinated is necessary to keep MIS-C incidence rates low. While SARS-CoV-2 is circulating in the world, MIS-C will remain as a differential diagnosis in the evaluation of sick children.