Pseudomonas aeruginosa (PA), a nonlactose fermenting gram-negative bacillus, is a common cause of nosocomial infections in critically ill or debilitated patients, particularly ventilator-associated pneumonia (VAP), and infections of bloodstream, urinary tract, intra-abdominal, wounds/skin/soft tissue. PA rarely affects healthy individuals, but may cause serious infections in patients with chronic structural lung disease, comorbidities, advanced age, impaired immune defenses, or with medical devices (e.g., urinary or intravascular catheters, foreign bodies). Treatment of pseudomonal infections is difficult, as PA is intrinsically resistant to multiple antimicrobials, and may acquire new resistance determinants even while on antimicrobial therapy. Mortality associated with pseudomonal VAP or bacteremias is high (> 35%) and optimal therapy is controversial. Over the past three decades, antimicrobial resistance among PA has escalated globally, via dissemination of several international multidrug-resistant “epidemic” clones. We review the emergence of antimicrobial resistance to this pathogen, and discuss approaches to therapy (both empirical and definitive).