Fluoroquinolone-based antibacterial chemoprophylaxis administered in situations in which the prevalence of fluoroquinolone-resistant Escherichia coli is low (<3% to 5%) can reliably reduce the risk for invasive gram-negative bacillary infection, and, if supplemented by gram-positive agents such as rifampin, penicillin, or macrolides, can reduce the risk of developing invasive infections caused by gram-positive microorganisms, including Viridans streptococci and coagulase-negative staphylococci. In the published literature, fluoroquinolone-based chemoprophylaxis does not reliably reduce the incidence of febrile neutropenic episodes, neutropenic episode-related mortality, or physician-initiated systemic antimicrobial prescribing behavior. Prophylaxis should only be prescribed in defined patient populations from the first day of cytotoxic therapy until neutrophil regeneration in environments in which the prevalence of gram-negative bacillary resistance to the prophylaxis strategy is low. Small phase II clinical trials suggest that empirical antibacterial therapy of unexplained fevers in neutropenic patients receiving effective fluoroquinolone-based prophylaxis under defined epidemiologic circumstances may be safely discontinued early. Better discriminators of infection in febrile neutropenic patients are needed.