Background: Since its initial description in December 2019 in Wuhan, China, coronavirus disease 2019 (COVID-19) has rapidly progressed into a worldwide pandemic, which has affected millions of lives. Unlike the disease in adults, the vast majority of children with COVID-19 have mild symptoms and are largely spared from severe respiratory disease. However, thereare children who have significant respiratory disease, and some may develop a hyperinflammatory response similar to thatseen in adults with COVID-19 and in children with Kawasaki disease (KD), which has been termed multisystem inflammatory syndrome in children (MIS-C).Objective: The purpose of this report was to examine the current evidence that supports the etiopathogenesis of COVID-19 in children and the relationship of COVID-19 with KD and MIS-C as a basis for a better understanding of the clinical course, diagnosis, and management of these clinically perplexing conditions.Results: The pathogenesis of COVID-19 is carried out in two distinct but overlapping phases of COVID-19: the first triggered by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) itself and the second by the host immune response. Children with KD have fewer of the previously described COVID-19–associated KD features with less prominent acute respiratory distress syndrome and shock than children with MIS-C.Conclusion: COVID-19 in adults usually includes severe respiratory symptoms and pathology, with a high mortality. Ithas become apparent that children are infected as easily as adults but are more often asymptomatic and have milder diseasebecause of their immature immune systems. Although children are largely spared from severe respiratory disease, they canpresent with a SARS-CoV-2–associated MIS-C similar to KD.