Invasive fungal diseases (IFDs), in particular invasive mold infections, still pose considerable problems in the care of children and adolescents treated for cancer or undergoing hematopoietic cell transplantation. As these infections are difficult to diagnose, and the outcomes for IFDs are still unsatisfactory, antifungal prophylaxis has become an important strategy in the clinical setting. Antifungal prophylaxis is indicated in patients at high risk for IFD, which is commonly defined as a natural incidence of at least 10%. As there is a growing interest in pediatric-specific clinical trials and pediatric-specific guidelines, this review focuses on the available data of mold-active antifungal prophylaxis in children and adolescents. The data demonstrate that a major effort is needed to characterize the pediatric patient population in which the net effect of prophylactic antifungals will be beneficial as well as to find the optimal prophylactic antifungal compound and dosage.