Inappropriate empirical antibiotic therapy for severe infections in the intensive care unit is a modifiable prognostic factor that has a great effect on patient outcome and health care resources. Inappropriate treatment is usually associated with microorganisms resistant to the common antibiotics, which must be empirically targeted when risk factors are present. Previous antibiotic exposure, prolonged length of hospital stay, admission category, local susceptibilities, colonization pressure, and the presence of invasive devices increase the likelihood of infection by resistant pathogens. Consideration of issues beyond in vitro susceptibility, such as antibiotic physicochemistry, tissue penetration, and pharmacokinetic/pharmacodynamic-driven dosing, is mandatory for the optimization of antibiotic use.