In the last decades, advances in early diagnosis and prompt management of febrile neutropenia have markedly improved the outcome of infections in cancer patients. New anticancer chemotherapy and immunomodulating agents have extended the risk and spectrum of opportunistic infections beyond neutropenia in cancer patients. Febrile neutropenia is a medical emergency requiring prompt initiation of empirical therapy with broad-spectrum antibiotics, based on local epidemiology. Low-risk neutropenic patients can be treated as outpatients with a beta-lactam/ ciprofloxacin combination or with moxifloxacin monotherapy. In neutropenic cancer patients with persistent fever, empirical antigungal therapy is recommended. Workup includes reassessment of antibacterial spectrum and therapeutic drug monitoring of blood concentrations, measurement of noninvasive fungal biomarkers, radiologic imaging and microbiologic/ histologic sampling of deep-seated sites of infection.