Infectious complications are still a major cause of morbidity and mortality in pediatric patients undergoing therapy for malignancy. Therapy-induced neutropenia is the most important risk factor for infectious risk in pediatric patients with cancer, but other factors, such as alterations in skin/mucosal barriers, and defects in cell-mediated or humoral immunity also contribute to the risk for infection. In most centers, about two thirds of bacteremic isolates are gram-positive pathogens, whereas gram-negative organisms are isolated less frequently, but are associated with considerably higher mortality rates. Prolonged neutropenia increases the risk for invasive fungal infection. In most cases, fever is an important and early indication of serious infection, particularly in children with neutropenia. Discrimination between serious and inconsequential infection in febrile children with neutropenia at the time of presentation is difficult, and serum markers have not been proven to reliably indicate infection. Although several groups investigate risk categories based on clinical tests or the genetic background, the current paradigm is to treat all pediatric patients with neutropenia and fever with intravenous broad-spectrum antibiotics. It is hoped that the identification of one or more predictive factors may be useful for tailoring antibiotic prophylaxis and therapy in children with cancer.