Preventive strategies besides the use of prophylactic antibiotic or antifungal regimens are fundamental ingredients of infection control in pediatric hematology-oncology patients. The clinical spectrum and the routes of transmission of infectious diseases in children have to be considered and preventive strategies should be adjusted to host dependent risk factors, in particular to the degree and duration of severe immunosuppression (i.e. neutropenia). This article overviews practical guidelines to prevent exposure and to reduce external sources of infection in immunocompromised children. Scientific evidence from controlled randomized studies is lacking or incomplete for many of these measures. A systematic and pragmatic approach to the critical control points of patient care in pediatric hematology/oncology is prudent to solve this problem in clinical practice. The corresponding recommendations are categorized in IV different levels of evidence.