Infection is the most common complication of chemotherapy-induced neutropenia. Bacterial infections predominate during the early stages of a neutropenic episode, whereas invasive fungal infections tend to occur later. The epidemiological pattern of bacterial infection continues to evolve globally and locally at the institutional level, as do patterns of susceptibility and resistance. These trends are often associated with local treatment practices and have a significant effect on the nature of empirical antibiotic therapy. The increasing rates of antimicrobial resistance among both gram-positive and gram-negative pathogens isolated from patients with neutropenia are posing new challenges. These challenges are compounded by the fact that relatively few new drugs are being developed, particularly those that treat resistant gram-negative organisms. They also stress the increasing importance of prevention and control of infection and stewardship of antibiotics as strategies in the overall treatment of patients with febrile neutropenia. The recognition of a subset of low-risk patients with neutropenia has created new opportunities (e.g., outpatient and oral therapy) and new challenges (e.g., infrastructure, safety, and compliance). These challenges may be met, to some extent, by appropriately adapting national guidelines to local and institutional circumstances.