In febrile neutropenic patients, prompt empiric antimicrobial intervention is mandatory. Numerous studies have demonstrated the benefit of broad-spectrum beta-lactams active against Gram-negative aerobes as well as against streptococci and Staphylococcus aureus in this setting. With this interventional strategy, a reduction of infection-related mortality to < or = 10% of patients undergoing intensive remission induction or consolidation chemotherapy could be obtained. Thereby, subgroups of patients have been identified who require an empiric modification of antimicrobial treatment, e.g., patients with catheter-related infections, with pulmonary infiltrates, or with unexplained fever (FUO) not responding to first-line antibacterials. In two consecutive, prospectively randomized trials conducted by the German Paul Ehrlich Society it could be shown that empiric antifungal therapy is beneficial for second-line treatment in patients with persistent FUO and improves first-line treatment results in patients with lung infiltrates. The addition of glycopeptides, however, should be restricted to patients with catheter-related infections due to coagulase-negative staphylococci or with infections due to multiresistant Gram-positive pathogens.