Pneumonia complicates hospitalization in 0.5 to 2.0% of patients and is associated with considerable morbidity and mortality. Risk factors for hospital-acquired pneumonia (HAP) include mechanical ventilation for > 48 h, residence in an ICU, duration of ICU or hospital stay, severity of underlying illness, and presence of comorbidities. Pseudomonas aeruginosa, Staphylococcus aureus, and Enterobacter are the most common causes of HAP. Nearly half of HAP cases are polymicrobial. In patients receiving mechanical ventilation, P aeruginosa, Acinetobacter, methicillin-resistant S aureus, and other antibiotic-resistant bacteria assume increasing importance. Optimal therapy for HAP should take into account severity of illness, demographics, specific pathogens involved, and risk factors for antimicrobial resistance. When P aeruginosa is implicated, monotherapy, even with broad-spectrum antibiotics, is associated with rapid evolution of resistance and a high rate of clinical failures. For pseudomonal HAP, we advise combination therapy with an antipseudomonal beta-lactam plus an aminoglycoside or a fluoroquinolone (eg, ciprofloxacin).