Newer beta-lactam antibiotics with high levels of activity against gram-negative aerobic bacilli (including Pseudomonas aeruginosa) such as cefoperazone, ceftazidime, imipenem, and aztreonam may be suitable for monotherapy of gram-negative pneumonia. Aminoglycoside antibiotics (gentamicin, tobramycin, amikacin are also highly active against these same organisms and have been more extensively used, but are both ototoxic and nephrotoxic. Key therapeutic questions are whether beta-lactams can safely replace aminoglycosides for the treatment of gram-negative pneumonia, and whether monotherapy or aminoglycoside and beta-lactam combination antibiotic treatment is superior. There is remarkably little definitive clinical data in the literature to answer these questions, but available studies suggest that beta-lactam monotherapy may be adequate for Escherichia coli and Klebsiella pneumoniae pneumonias, but that combination therapy may be preferred for Pseudomonas aeruginosa, Serratia sp, Enterobacter sp, and Acinetobacter sp, largely based on rates of bacterial persistence and emergence of resistance. At this time, there are more data available to support aminoglycoside monotherapy than beta-lactam monotherapy in gram-negative pneumonia and remarkably little data to suggest superiority of two antibiotics over single agents when they have been compared prospectively. Thus, combination therapy remains a conservative recommendation until better studies are available.