OBJECTIVE The effect of acute coronavirus disease 2019 (COVID-19) on morbidity and mortality in children has been relatively small. If a child presents to my office with persistent fever and systemic hyperinflammation but no known exposure to COVID-19, how likely are they to have multisystem inflammatory syndrome in children (MIS-C)? What is currently known about MIS-C and what is the prognosis for children affected by it? CONCLUSIONS Amid the COVID-19 pandemic, the emergence of a novel condition presents yet another challenge to clinicians, public health professionals, and the pediatric population. Multisystem inflammatory syndrome in children is a rare but potentially severe condition seen in children with evidence of COVID-19 approximately 2 to 6 weeks before symptom onset. Common signs and symptoms include persistent fever, systemic hyperinflammation, gastrointestinal symptoms (eg, abdominal pain, vomiting, diarrhea), mucocutaneous changes (eg, rash, conjunctivitis), headache, or cardiac dysfunction. As many children present as asymptomatic or with mild symptoms of COVID-19, the development of MIS-C can seem sudden and surprising to families and providers. Although children with MIS-C usually require hospitalization, the outcomes are largely favourable with prompt recognition and intense therapy.