Recent reports of acute hepatitis of unknown origin in previously healthy children have been increasing worldwide. The main characteristics of the affected children were jaundice and gastrointestinal symptoms. Their serum aminotransaminase levels were above 500 IU/L, with negative tests for hepatitis viruses A-E. By 31 May 2022, the outbreak had affected over 800 children under the age of 16 years in more than 40 countries, resulting in acute liver failure in approximately 10%, including at least 21 deaths and 38 patients requiring liver transplantation. There was still no confirmed cause or causes, although there were several different working hypotheses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), adenovirus serotype 41, or SARS-CoV-2 superantigen-mediated immune cell activation. Here, we review early observations of the 2022 outbreak which may inform diagnosis, treatment, and prevention in the context of an overlapping COVID-19 pandemic.