Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) can be caused by a wide variety of bacteria that originate from the patient flora or the health care environment. We review the medical and microbiology literature and the results of the SENTRY Antimicrobial Surveillance Program (1997-2008) to establish the pathogens most likely to cause HABP or VABP. In all studies, a consistent 6 organisms (Staphylococcus aureus [28.0%], Pseudomonas aeruginosa [21.8%], Klebsiella species [9.8%], Escherichia coli [6.9%], Acinetobacter species [6.8%], and Enterobacter species [6.3%]) caused approximately 80% of episodes, with lower prevalences of Serratia species, Stenotrophomonas maltophilia, and community-acquired pathogens, such as pneumococci and Haemophilus influenzae. Slight changes in the pathogen order were noted among geographic regions; Latin America had an increased incidence of nonfermentative gram-negative bacilli. In addition, VABP isolates of the same species had a mean of 5%-10% less susceptibility to frequently used extended-spectrum antimicrobials, and the rate of drug resistance among HABP and VABP pathogens has been increasing by 1% per year (2004-2008). In conclusion, the empirical treatment of HABP and VABP due to prevailing bacterial causes and emerging drug resistance has become more challenging and requires use of multidrug empirical treatment regimens for routine clinical practice. These facts have profound impact on the choices of comparison therapies to be applied in contemporary new drug clinical trials for pneumonia.