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ABSTRACT Background: Over the course of the severe acute respiratory syndrome coronavirus 2 (‘SARS-CoV-2’) pandemic spread, case reports of pediatric patients presenting with delayed systemic inflammation and multi-organ dysfunction emerged. This newly described syndrome was defined as Multisystem Inflammatory Syndrome in Children (‘MIS-C’). Objectives: The aim of this paper is to provide a comprehensive literature review on the novel syndrome termed MIS-C and its definition, epidemiology, clinical presentation, diagnostic evaluation, pathophysiology, and treatment. Methods: A literature search was conducted through Pubmed on June 5, 2021, with updated searches until August 17, 2021. Of the 1,000 identified publications, 44 articles were included in this literature review after screening by title, abstract, and full text for eligibility, relevance, and risk of bias, and manual assessment of the reference lists. Results: MIS-C is a hyperinflammatory syndrome that develops 2 to 5 weeks after SARS-CoV-2 infection and likely results from an immune-mediated post-infectious response. The reported incidence of MIS-C is low and shows an overrepresentation in minority communities. The clinical presentation is characterized by persistent fever with multi-organ dysfunction, including gastrointestinal, mucocutaneous, cardiovascular, neurological, and respiratory symptoms. Most MIS-C patients have elevated inflammatory markers and positive serology for SARS-CoV-2. Children under investigation for MIS-C should be managed by a multidisciplinary team in a center with pediatric intensive care capabilities. Initial treatment involves resuscitation, intravenous immunoglobulin, anticoagulation, and the consideration of corticosteroids. Based on the limited evidence to date, MIS-C appears to have a favorable outcome with low mortality and few residual sequelae. Conclusion: MIS-C is a rare, but potentially life-threatening syndrome occurring after SARS-CoV-2 exposure in pediatric patients. Prompt recognition, multidisciplinary management, and close follow-up are crucial to reducing morbidity and mortality.