There remains a consensus for early empirical therapy in febrile neutropenic patients. Many trials over the past decade have demonstrated the efficacy of broad spectrum, single agent therapy. With the shift in bacteria causing infections from Gram-negative to Gram-positive in these patients, the provision of specific therapy for these latter organisms has been examined in a variety of studies with differing results. The strategy of giving empirical amphotericin B to patients with persistent fever has become established over the past 10 years, but there is concern that this is no longer valid in many patients receiving systemic prophylaxis with azole antifungal agents. This review examines the various strategies for therapy and choice of agents and makes recommendations for initial therapy and modification.