Over the past several decades, there has been substantial progress in the management of patients with febrile neutropenia. However, the ever-changing patterns of infection, ecology, and antibiotic-resistance trends do not allow the development of treatment guidelines that could be applied universally. Hence, the institution's predominant pathogens and resistance patterns should guide the empirical choice of antimicrobials. Prompt initiation of antimicrobial therapy remains the gold standard. Monotherapy with the newer broad-spectrum antimicrobials has tended to replace the classic combination therapy. Empirical administration of glycopeptides, such as vancomycin, without documentation of a gram-positive infection is not favored. The development of risk-stratification models has allowed for identification of low-risk patients with additional treatment options, such as early discharge and exclusively outpatient treatment with oral antimicrobials. The initiation of empirical antifungal therapy in persistently febrile neutropenic patients has become common practice, especially recently, since the introduction of new, effective, less toxic antifungal drugs. It is hoped that the development of new nonculture-based diagnostic methods will allow for the early detection of invasive fungal infections and, thus, the replacement of empirical antifungal therapy with pathogen-specific, preemptive therapy. Cancer 2005. © 2005 American Cancer Society.