Febrile neutropenia is a syndrome commonly anticipated in patients receiving treatment for cancer. Its management for the last three decades has included the prompt administration of empiric antibacterial therapy, which resulted in a reduction in mortality. Challenges remain the administration of the most appropriate empiric treatment regimen adapted to evolving and changing epidemiology of infections in neutropenic patients and resistance rates; the development of markers of early diagnosis of severe bacterial or fungal infections; the risk stratification of patients; the establishment of targeted empiric (preemptive) antifungal therapy criteria; and the containment of antimicrobial resistance that compromises effective treatment efforts, through effective antibiotic policies and implementation of infection control measures, especially hand hygiene. The need for targeted antimicrobial or antifungal prophylaxis and supportive strategies like the use of growth factors awaits further clarification.