Since the discovery of penicillin, pharmaceutical companies have produced more than 100 antibacterial agents/antibiotics to combat a wide variety of bacterial infections. The major classes of antibacterial agents are β-lactams (including penicillins, cephalosporins, monobactams, carbapenems), aminoglycosides, tetracyclines, sulfonamides, macrolides (such as erythromycin), quinolones, and glycopeptides (e.g. vancomycin). By the 1980s, with the use of these antibacterial agents, improved sanitary conditions, and the extensive refrigeration of food, it was believed that industrialized nations had won the war against pathogenic microbes. However, in the past several years, the rapid emergence of bacterial resistance to antibiotics has been observed. The extensive use (and misuse) of antibiotics has provided powerful forces for the selection of microbes that either carried mutations conferring resistance or had the enhanced ability to mutate to resistance in the face of the antibiotic. Bacteria have mutated or have acquired new genes producing novel machinery to overcome the action of many antibiotics. In recent years, many new antibiotic-resistant strains have been isolated from patients throughout the world. Emergence of bacterial resistance to a number of antimicrobial agents such as β-lactam antibiotics, macrolides, quinolones, and vancomycin is becoming a major worldwide health problem. The most significant problem in clinical practice is the increase in the isolation of methicillin-resistant Staphylococcus aureus (MRSA) strains. In a recent MRSA surveillance study conducted in Japan, more than 60% of hospital S. aureus isolates were found to be methicillin resistant. About 68% of the MRSA in Japan in 1992 were also found to carry multiple drug resistance determinants. In the United States, by the early 1990s, MRSA was detected in 20-40% of all S. aureus hospital isolates reported to the National Nosocomial Infections Surveillance (NNIS) System and is also a big problem in long-term care facilities. Other than United States and Japan, the occurrence of epidemic strains of MRSA has also been reported in many countries such as Argentina, Australia, Belgium, Canada, Denmark, France, Germany, Greece, Hong Kong, Italy, Malaysia, Netherlands, New Zealand, Portugal, Spain, Sweden, Taiwan, and the United Kingdom. In addition to resistance to β-lactam antibiotics, multiply resistant MRSA are also resistant to macrolides, tetracyclines, aminoglycosides, and fluoroquinolones. At present, the only effective treatment for multiply resistant MRSA infections is vancomycin. However, the minimum inhibitory concentration (MIC) for vancomycin against some MRSA isolates has been increasing recently, leading to a situation where standard doses of vancomycin may not be effective for deepseated infections. Enterococci are generally fairly resistant to antibiotics such as penicillins, cephalosporins, and aminoglycosides. Current treatment for enterococcal infection is the use either of a combination of two antibiotics or of vancomycin alone. However, with the recent increase use of vancomycin in MRSA infections and colitis due to Clostridium difficile, multiply resistant Enterococcus faecium has emerged. In a recent report to CDC's NNIS, the percentage of nosocomial enterococci resistant to vancomycin increased from 0.3% in 1989 to 7.9% in 1993. In ICUs, the percentage of enterococcal isolates resistant to vancomycin increased from 0.4% in 1989 to 13.6% in 1993. Because of the fact that not many drugs can be used effectively to treat enterococcal infections, treatment options for patients infected with vancomycin-resistant enterococci are very limited. The transfer of the vanA resistance gene from enterococci to S. aureus to generate vancomycin-resistant S. aureus has been demonstrated in the laboratory. Although a clinical strain of vancomycin-resistant S. aureus has not been isolated to date, vancomycin resistance in coagulase-negative staphylococci such as Staphylococcus hemolyticus has been reported. Furthermore, the Gram-negative organisms such as Pseudomonas, Klebsiella, Proteus, and Enterobacter species were the important antibiotic resistant pathogens in the 1970s; they remain a problem in some hospitals today. Apart from the nosocomial pathogens described above, the resistance of the important community-acquired pathogen Streptococcus pneumoniae to penicillin and other antibacterials is becoming a worldwide problem. Multidrug-resistant strains of Mycobacterium tuberculosis have emerged in several countries including the United States. The emergence and spread of resistant nosocomial and community-acquired pathogens is generating a great threat to public health worldwide. There is an urgent need to develop new agents to treat patients infected with these multidrug-resistant bacteria. This review summarizes a number of research directions in antibacterial discovery that may be able to address and overcome the problem of emergence of multidrug-resistant bacteria.