Different approaches have developed over time regarding the empirical antimicrobial therapy of fever in neutropenic patients. The use of intravenous antibiotics remains the standard approach. Clinical criteria and ‘low-risk’ prediction rules have been developed that help select patients in whom oral therapy is well tolerated and who may be eligible for outpatient management. Comorbidity and clinical status at presentation remain important criteria in the risk-assessment process. Outpatient management requires additional assessment of non-medical criteria. Patients without documented infection and who have responded to initial therapy may benefit from simplified therapy such as a switch to oral drugs and/or outpatient management. Discontinuation of therapy may be considered in selected cases. Risk assessment in neutropenic patients with persistent unexplained fever is challenging. Available data suggest that broadening of the antibacterial coverage is of limited value. Instead, definition of the risk of fungal infection by using clinical criteria, imaging and laboratory studies, as well as the identification of those patients likely to benefit from antifungal therapy, appear to be of critical importance.