Heart transplantation is an accepted therapy for end-stage heart disease in children and adults. Over the past 25 years, the perioperative and 1-year mortality has steadily improved, leading to an increased focus on midterm and late-term complications. Cardiac allograft vasculopathy (CAV) is the leading cause of late graft loss in children. The prevalence of disease increases steadily after transplantation from 5% at 2 years to 35% by 10 years according to multiple database analyses. Allograft vasculopathy is the end point of a complex interaction of stimuli including chronic rejection, endothelial dysfunction, infection, and traditional cardiac risk factors. While an increased understanding of risks associated to CAV has led to more aggressive surveillance approaches, the rates of CAV remain high and outcomes after diagnosis of CAV are very poor with up to 50% of children suffering graft loss or death within 2 years of diagnosis. In an attempt to combat the development and progression of CAV, multiple medical and interventional strategies have been utilized. Pharmacologic approaches have focused on the use of various immunosuppressants and adjuvant medications to combat inflammation and immune mediated graft injury. While randomized controlled trials are rare in pediatric heart transplant cohorts, sufficient adult data have been developed in both controlled and observational trials to provide a framework for the prevention and management of patients with CAV. However, none of these interventions have been shown to be effective in significantly prolonging graft survival and retransplantation remains the only reliable therapy for severe CAV.