Pseudomonas aeruginosa carries a notably higher mortality rate than other pneumonia pathogens. Because of its multiple mechanisms of antibiotic resistance, therapy has always been challenging. This problem has been magnified in recent years with the emergence of multidrug-resistant (MDR) pathogens often unharmed by almost all classes of antimicrobials. The objective of this article is to assess optimal antimicrobial therapy based on in vitro activity, animal studies, and pharmacokinetic/pharmacodynamic (PK/PD) observations so that evidence-based recommendations can be developed to maximize favorable clinical outcomes. Mechanisms of antimicrobial resistance of P aeruginosa are reviewed. A selective literature review of laboratory studies, PK/PD concepts, and controlled clinical trials of antibiotic therapy directed at P aeruginosa pneumonia was performed. P aeruginosa possesses multiple mechanisms for inducing antibiotic resistance to antimicrobial agents. Continuous infusion of antipseudomonal β-lactam antibiotics enhances bacterial killing. Although the advantages of combination therapy remain contentious, in vitro and animal model studies plus selected meta-analyses of clinical trials support its use, especially in the era of MDR. Colistin use and the role of antibiotic aerosolization are reviewed. An evidence-based algorithmic approach based on severity of illness, Clinical Pulmonary Infection Score, and combination antibiotic therapy is presented; clinical outcomes may be improved, and the emergence of MDR pathogens should be minimized with this approach.