Infections are the most important causes of morbidity and mortality in patients with aggressive malignancies and those undergoing allogeneic stem cell transplantation. The introduction of new therapeutic approaches including the use of nucleoside analogs and of monoclonal antibodies to CD20 and CD52 and the increased use of matched unrelated stem cell donors has resulted in new challenges with regard to systemic viral and fungal infections. In patients with bacterial infections, emergence of resistance to formerly widely used antibiotics as well as a shift of causative pathogens towards a predominance of multi-resistant gram-positive cocci has to be taken into consideration. In high-risk neutropenic patients with fever of unknown origin, prompt empiric monotherapy with piperacillin-tazobactam, cefepime, ceftazidime, or a carbapenem is mandatory. In patients with lung infiltrates, early preemptive intervention with an antifungal active against aspergilli is recommended, whereas in patients with catheter-related, skin or soft tissue infections, preemptive addition of a glycopeptide shows a high response rate. The prompt preemptive use of ganciclovir or foscarnet in allogeneic stem cell transplant recipients can reliably be guided by serial monitoring of cytomegalovirus antigen and polymerase chain reaction monitoring.