Infections are a major cause of morbidity and mortality among immunocompromised patients. This report discusses bacterial and mycotic infections prophylaxis in the granulocytopenic patients with hematologic malignancies. Various strategies have been derived to prevent the infections: a combination of oral antibacterial and antifungal prophylaxis with quinolones and newer azoles (fluconazole, itraconazole), high efficiency particulate air filtration, protective isolation and management of central venous catheter. However, the emergence of antibiotic resistant organism continues to pose a major challenge to the successful eradication and prevention of infections in neutropenic host, and demands the development of innovative approaches to antibiotic use and infection control procedures.