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In the spring of 2020, a series of reports from Europe and the USA described clusters of children and adolescents presenting with a life-threatening, hyperinflammatory syndrome — called ‘multi-system inflammatory syndrome in children’ (MIS-C) — that was seemingly linked to prior exposure to the coronavirus SARS-CoV-2. In June 2020, the US National Institutes of Health convened a workshop of immunologists and clinicians to discuss emerging knowledge and identify key questions surrounding MIS-C, with a focus on innate and adaptive immunity, genetics and epigenetics. This Meeting Report describes the main findings from the workshop.