Outcomes following cardiac transplantation in childhood continue to improve. Advances in immunosuppressive therapy over the past two decades likely have contributed to this trend. The evolution in the management of immunosuppression in children has been based on clinical experience rather than on evidence-based medicine; indeed, there have been no pivotal randomized controlled trials of any form of immunosuppression in pediatric thoracic transplantation. Important trends in immunosuppressive therapy and transplant outcomes have been obtained from large transplant registries. Several trends have been identified since the last review of this topic in this journal. First, there is increased knowledge of the pharmacodynamics and pharmacokinetics of immunosuppressive drugs in children, with notable advances in the field of pharmacogenomics. These studies help explain individual variations in drug exposure, efficacy, and adverse events. They also help explain racial and ethnic variations in drug metabolism and efficacy. Second, there have been clear trends in the use of specific immunosuppressive medications. Use of induction therapy, especially polyclonal T cell–depleting antibody preparations, has increased significantly in recent years. The calcineurin inhibitor (CNI) tacrolimus is being used as the cornerstone of maintenance therapy in lieu of cyclosporine in more and more centers. Mounting evidence suggests that use of adjunctive agents (notably mycophenolate mofetil [MMF]) may improve outcomes, including survival, suggesting that monotherapy with CNIs is not the ideal maintenance therapy. Despite its increased cost, MMF has largely replaced azathioprine as the adjunctive agent of choice. Inhibitors of the mammalian target of rapamycin (i.e., sirolimus and everolimus) have not yet assumed a major place as adjunctive agents, as their safety and efficacy have not been well established in children. With the improvements in immunosuppressive therapy, the justification for routine corticosteroid use is far from clear, and many centers have shown excellent outcomes with complete steroid avoidance. Third, there is increasing interest in the importance of anti-HLA antibodies as important risk factors for adverse graft and patient outcomes. This is generating intense interest in treatments that target B cells and plasma cells. Finally, there is increasing realization that the “one size fits all” approach to immunosuppressive therapy is an obsolete concept and that the ultimate goal is to tailor immunosuppressive therapy to the needs of the individual patient. The development of reliable biomarkers of the patient’s immune response to the allograft will be essential for optimal individualized immunosuppressive management.