The IRIS was initially described in HIV-positive patients as a sudden clinical deterioration after the introduction of highly active retroviral therapy. It is believed that IRIS is caused by a restored and exaggerated inflammatory immune response to different infectious or non-infectious triggers. This abnormal response is the consequence of an imbalance between pro-inflammatory and anti-inflammatory states. Recently, IRIS has also been reported in adult SOT recipients, causing local and systemic manifestations, and compromising long-term graft function and patient survival. However, IRIS has to date not been reported in pediatric SOT recipients. Here we review what is known and speculated about the pathogenesis of IRIS and propose that children may be relatively protected from IRIS.