Despite significant advances in supportive care, infection remains second only to malignancy as a cause of death in pediatric oncology patients, and infection accounts for a large fraction of treatment-related costs. Multiple risk factors contribute to infection-related morbidity, chief among them the immunosuppressive effects of leukemia itself and of cytotoxic chemotherapy, prolonged hospitalization and antibiotic use, and loss of barrier integrity associated with mucositis and the need for indwelling central access. While viruses are the most common causes of infection, bacteria are responsible for most life-threatening complications. Gram-negative bacilli are a concern for all patients undergoing treatment, while a subset of gram-positive organisms, particularly viridans streptococci, become significant pathogens in children receiving profoundly immunosuppressive therapy. Invasive fungal infections are also a serious risk for morbidity and mortality in this population. Availability of new antimicrobial agents has made it possible to treat infectious complications more effectively, but their availability is also leading to an increased prevalence of highly resistant pathogens. Future work in pediatric oncology will need to include measures to reduce the immunosuppressive effects of anti-cancer therapy, provide targeted treatment for infections, and better identify groups of patients at high risk for infectious complications, who may benefit from antimicrobial prophylaxis or more aggressive empirical therapy.