Nosocomial pneumonia is the leading cause of mortality among the infections produced by multi-resistant microorganisms in intensive care units (ICU). The solution of this problem created by the colonization and infection of the respiratory tract is beyond respiratory medicine and requires a multi-disciplinary approach, involving other nosocomial infections in the ICU. Up to 80% ICU patients receive antibiotics for severe infections or prophylactically, frequently with no clear justification for these treatments. The extended use of antibiotics increases the problem by exerting a selective pressure favoring the development of resistant organisms. Some evidences suggest that the infections produced by multi-resistant pathogens increase the mortality of nosocomial pneumonia. The following mechanisms are responsible for the acquisition of resistance: alteration of bacterial wall permeability; production of inactivating enzymes, modification of the target site, or eflux. Resistance is genetically transmitted by chromosomes or by plasmids. At the present time staphylococci (Staphylococcus aureus and coagulase-negative staphylococci) and enterococci predominate among the gram-positives, and non-fermenters (Pseudomonas aeruginosa, Acinetobacter spp) and some Enterobacteriaceae among the gram-negatives. Antibiotics are the main determinants of the problem of resistance but also partially their vehicle. The solution of this problem includes infection control, diagnosis and adequate therapy (sufficient doses chosen according to the case and based on prefixed antibiotic politics). These antibiotic politics imply a rational use, reconsideration of the initial scheme according to microbiologic results, limited use of combination antimicrobial strategies, restricted list of drugs, rotation and correct use of prophylaxis.