The rapid institution of empirical broad-spectrum antibiotics has become the gold standard of treatment for febrile neutropenic children undergoing therapy for cancer. With this approach, morbidity and mortality have dropped significantly but have not been eliminated altogether. In recent randomized studies evaluating different drug combinations, there is still a 3-10 % mortality reported in febrile, neutropenic cancer events. Despite improvements in invasive and non-invasive diagnostic procedures, a majority of patients will receive antibiotic therapy despite an inability to identify a specific pathogen or source (fever of unknown origin, FUO). While there are evidence-based guidelines in adult patients with fever and neutropenia, data are less clear in the pediatric population. Experts agree on the early use of empirical antibiotic therapy, which covers Pseudomonas spp. and is initiated at the first sign of fever. The success of this approach has been based upon clinical intervention before the results of the diagnostic evaluation are available. In contrast, the use of aminoglycosides or glycopeptides is still a matter of debate, as it is the duration of antibiotic therapy. Based on published data in pediatric and adult patients with cancer, the current diagnostic procedures and therapeutic strategies will are discussed. The recommendations given are a consensus of the German Society of Pediatric Oncology and Hematology (GPOH) and the German Society of Pediatric Infectious Diseases (DGPI).