Purpose of review: The authors review the evolution of immunosuppression on ABO incompatible pediatric liver transplant focusing on early and more recent experience crossing blood groups. Combinations of medications with different mechanisms of action has led to aggressive protocols, commonly used in children. With the availability of newer drugs, however, more selective strategies have been proposed in these recipients on order to limit the side effects related to excessive immunosuppression. Recent findings: Over the past decade a better understanding of transplant immunology and availibility of more effective immunosuppressive drugs has allowed crossing blood barriers in pediatric liver transplantation with more confidence and the support of progressively improved results. Summary: Immunosuppressive therapy for ABO-incompatible pediatric liver transplants is evolving towards minimization, reflecting a general tendency in organ transplantation.