Importance: After a cluster of pediatric cases of hepatitis of unknown etiology were identified in Scotland in March 2022, the World Health Organization published an outbreak alert, and more than 1010 probable cases were reported. Some cases progressed to acute liver failure and required liver transplant. Although many patients had positive results for adenovirus on polymerase chain reaction testing from whole blood samples and/or reported recent COVID-19 infection (with or without seropositivity), the precise pathogenesis remains unclear despite the high potential morbidity of this condition. Objective: To summarize the currently available evidence regarding novel pediatric hepatitis of unknown etiology (or novel hepatitis), encompassing case numbers, testing, management, and outcomes. Evidence Review: A rapid review of the literature from April 1, 2021, to August 30, 2022, aimed to identify all available published case series and case-control studies of novel hepatitis. The search included PubMed and references and citations of short-listed studies. Findings: A total of 22 available case series and case-control studies describing 1643 cases were identified, with 120 children (7.3%) receiving liver transplants and 24 deaths (1.5%). Outcome reporting and testing for adenovirus and SARS-CoV-2 was incomplete. Assessment of disease severity and management was mixed and results regarding testing for adenovirus and SARS-CoV-2 were inconsistent for both serological testing and testing of explant or biopsy liver samples. More recent studies suggest a more plausible role for adenovirus and/or adeno-associated virus 2. Conclusions and Relevance: This systematic review without meta-analysis describes the challenge posed by hepatitis of unknown etiology in terms of investigation and management, with many cases progressing to acute liver failure. The lack of clarity regarding pathogenesis means that these children may be missing the potential for targeted therapies to improve outcomes and avert the need for transplant. Clinicians, immunologists, and epidemiologists must collaborate to investigate the pathogenesis of this novel hepatitis.