During the past few years there has been a remarkable increase in organisms that are resistant to several different groups of antimicrobials. These multi-drug resistant (MDR) bacteria cause an increasing number of infections each year, primarily in intensive care units. Increasing numbers of patients with impaired host defenses, use of new instrumentation and procedures, decrease in resources for infection control, and appearance of new organisms that previously were unrecognized are some of the reasons why MDR nosocomial pathogens have become increasigly important. Yet, use of antimicrobial agents is also a major influence on pattern of resistance in hospital organisms causing infection. Thus, measures to optimize use of antimicrobials for these patients have special importance. This requires a coordinated approach by prescriber, pharmacist, nurse, laboratorian, and the patient. The hospital purchasing and pharmacy/therapeutics groups determine the therapeutic agents that are available, and the pharmacy also can provide concurrent monitoring of dose and duration of therapy. The laboratory has an impact on initial empiric choice of drug through periodic summaries of the susceptibility patterns of likely pathogens in the hospital, and can decrease duration of empiric therapy by rapid turnaround of diagnostic testing results. A major impact can result from adoption of critical pathway or clinical guidelines, when these are developed as a cooperative effort. Maximizing benefits of therapy requires further evaluation of several issues. Among these are the value of cycling of antimicrobial therapy and use of combination therapy in delaying emergence of resistance. To assess these strategies, cooperative multi-center studies are needed in which selection and classification biases are addressed prospectively, and in which confounding factors are controlled. The problem will not be solved until the entire healthcare delivery system becomes involved in the campaign.