Bacterial infections are becoming more difficult to treat. At the present time c. 70% of nosocomial infections are resistant to at least one antimicrobial drug that previously was effective for the causative pathogen. Pathogens that are notorious for their virulence and ability to develop resistance include Staphylococcus aureus, Enterococcus spp., members of the Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter species. Notable resistance patterns that have emerged include methicillin resistance in S. aureus, which started in the healthcare setting but has now moved into the community. Vancomycin resistance in enterococci is frequently seen, and vancomycin resistance in methicillin-resistant S. aureus is a public health threat. Resistance patterns seen in pseudomonal and Acinetobacter infections are rapidly shifting. The situation has become sufficiently serious for clinical opinion leaders to call upon governments for assistance in addressing the problem. In this worsening environment, in which patients are at progressively greater risk of untreatable infections, clear recommendations for prescribers are urgently needed. Severity of infection and underlying conditions are key issues, as patients with the most serious diseases are those in most urgent need, and improvements in our ability to predict likely infecting pathogens when empirical therapy is necessary are needed. Risk-factors and local resistance patterns must be accounted for, and initial empirical therapy should be adequately broad spectrum and adequately dosed. Agents must be highly active, able to penetrate adequately to the site of infection, safe, and well-tolerated.