Pseudomonas aeruginosa is one of the leading causes of nosocomial infections. Severe infections, such as pneumonia or bacteraemia, are associated with high mortality rates and are often difficult to treat, as the repertoire of useful anti-pseudomonal agents is limited (some beta-lactams, fluoroquinolones and aminoglycosides, and the polymyxins as last-resort drugs); moreover, P. aeruginosa exhibits remarkable ability to acquire resistance to these agents. Acquired resistance arises by mutation or acquisition of exogenous resistance determinants and can be mediated by several mechanisms (degrading enzymes, reduced permeability, active efflux and target modification). Overall, resistance rates are on the increase, and may be different in different settings, so that surveillance of P. aeruginosa susceptibility is essential for the definition of empirical regimens. Multidrug resistance is frequent, and clinical isolates resistant to virtually all anti-pseudomonal agents are increasingly being reported. Monotherapy is usually recommended for uncomplicated urinary tract infections, while combination therapy is normally recommended for severe infections, such as bacteraemia and pneumonia, although, at least in some cases, the advantage of combination therapy remains a matter of debate. Antimicrobial use is a risk factor for P. aeruginosa resistance, especially with some agents (fluoroquinolones and carbapenems), and interventions based on antimicrobial rotation and restriction of certain agents can be useful to control the spread of resistance. Similar measures, together with the prudent use of antibiotics and compliance with infection control measures, are essential to preserve the efficacy of the currently available anti-pseudomonal agents, in view of the dearth, in the near future, of new options against multidrug-resistant P. aeruginosa strains.