During the last decade, both gram-positive and gram-negative bacteria that are resistant to most or all available antibacterial classes have become increasingly prevalent nosocomial pathogens, particularly among immunocompromised patients and those hospitalized in intensive care units. Among gram-positive bacteria, increasing concerns are posed for health care- and community-associated methicillin-resistant Staphylococcus aureus (MRSA), S aureus with reduced susceptibility to vancomycin, and vancomycin-resistant enterococci (VRE). A spectrum of newer antibacterial agents has been developed for the treatment of multi-resistant gram-positive bacteria, such as linezolid, tigecycline, daptomycin, and novel glycopeptides. Gram-negative bacteria have also developed multidrug resistance (MDR), which in the Enterobacteriacae is commonly due to the production of extended-spectrum beta-lactamases and carbapenemases of VIM, IMP, or KPC types. Currently, non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii are commonly resistant to all available antibiotics, including the newer agents. Colistin retains activity against most P aeruginosa and A baumannii, but its clinical use remains questionable, while newer carbapenems and tigecycline have limited additional advantages. Rational use of newer antibacterial agents coupled with enhanced infection control measures may be able to sufficiently control MDR organisms as to allow hematological patients to recover from serious infectious complications.