Hepatitis D virus (HDV) is an uncommon, defective, single-stranded circular RNA virus that is dependent on the hepatitis B virus' surface antigen envelope proteins for transmission. It is highly pathogenic and associated with high rates of progression to cirrhosis and associated complications. HDV continues to ravage endemic parts of Asia and Europe, and its prevalence in the United States, although low, has not decreased in frequency, despite universal hepatitis B virus vaccination, because of lack of testing and underrecognition. There are few reports on the prevalence and characteristics of HDV infection in the pediatric population. We present 2 patients with HDV infection at our institution; both were from eastern Europe and were treated with pegylated interferon-α. The present standard of care treatment for HDV yields suboptimal results, but insights into the virology of hepatitis D are stimulating the search for novel therapeutic approaches, particularly the development of prenylation inhibitors and viral entry inhibitors.