ABSTRACT: Children with hepatitis C virus infection often differ from adults regarding the rate of viral clearance, duration of infection, and the progression to cirrhosis. In the pediatric population, vertical transmission of hepatitis C virus infection from mother to infant is the most common route of infection. In the present review, we explore the factors that may influence the natural history of hepatitis C virus infection in children who acquire the infection through maternal–fetal transmission. There is particular focus on how viral diversity and the infant immune system may affect viral transmission. An enhanced understanding of maternal–fetal transmission of hepatitis C virus infection has the potential to affect effective drug and vaccine development for both children and adults.