Patients with bone marrow failure are at increased risk to develop severe infection. The main immunodeficiency is neutropenia, particularly in patients with acute leukemia and severe aplastic anemia. In addition, treatment-related immunodefficiencies further increase the risk of infection, including mucositis caused by intensive chemotherapy, and T-cell immunodeficiency that follows immunosuppressive therapies for aplastic anemia. In neutropenic patients, prophylactic strategies focus on the prevention of bacterial and fungal infections. A key element in the management is the prompt initiation of empiric antibiotic therapy in febrile neutropenic patients, focusing on Gram-negative bacteria. With this regard, the emergence infection caused by multi-drug resistant Gram-negative bacteria is a major challenge, because inappropriate antibiotic coverage is associated with high mortality rates. Therefore, it is imperative to know local epidemiology in order to select the most appropriate antibiotic regimen. Likewise, changes in the initial empiric antibiotic regimen should be driven by objective parameters and not just fever. For invasive fungal disease, while the empiric antifungal therapy is still used, this strategy has been replaced by a preemptive diagnostic-driven approach. In this strategy, serial (2–3×/week) serum galactomannan and chest tomograpy drive the start of antifungal therapy. Finally, while the wise and appropriate employment of all these strategies is very important, recovery from neutropenia is the main prognostic factor. Therefore, every efforts must be devoted to control the underlying disease.