Heart transplantation remains the only realistic therapeutic option for children with end-stage heart disease. The main indication for transplantation in children is severe heart failure (HF) associated with impaired function of the systemic ventricle. Extensive evidence supports the use of cardiopulmonary exercise testing to select patients with increased short-term mortality who should be offered transplantation. Transplantation for congenital heart disease illustrates best many of the peculiarities of heart transplant in the pediatric age group. The assessment of pulmonary vascular resistance (PVR) is particularly crucial in order to reduce the rate of right HF post-transplant, but it can be technically difficult, particularly in congenital heart disease. Maintenance therapy is commonly a combination of a calcineurin inhibitor (CNI) and cell cycle inhibitor. A problem in pediatric transplantation is the presence of pre-existing human leukocyte antigen (HLA) antibodies, which have been linked to increased hyperacute, cellular, and humoral rejection and increased mortality posttransplant.