Febrile neutropenia in immunocompromised hosts is associated with a high mortality. Empirical treatment in such cases is instituted to cover the common pathogens. Generally, combination antibiotic treatment is used early in the febrile neutropenia phase. Recent studies demonstrate that monotherapy with certain beta-lactam antibiotics can be equally effective. Glycopeptide antibiotics are used in the absence of an adequate response to the initial antibiotics. Empirical antifungal therapy may be given if fever does not settle in 72-96 h despite antibiotics. Newer antifungal agents have increased the available options for initial antifungal agents though more data are needed before any conclusive recommendation can be made. Recent changes in the epidemiology of multiresistant organisms necessitate local microbiological input into empiric policies with increasing need to consider cover for methicillin-resistant Staphylococcus aureus, glycopeptide intermediate S. aureus, vancomycin-resistant S. aureus, vancomycin-resistant enterococci, Gram-negative bacilli that produce extended-spectrum beta-lactamases, Stenotrophomonas maltophilia, and multi-resistant Acinetobacter baumanii.