The discovery, development, and clinical use of antibioticsduring the 20th century have decreased substantially the mor-bidity and mortality from bacterial infections. The antibioticera began with the therapeutic application of sulfonamidedrugs in the 1930s, followed by a “golden” period of discoveryfrom approximately 1945 to 1970, when a number of structur-ally diverse, highly effective agents were discovered and devel-oped (16). However, since the 1980s the introduction of newagents for clinical use has declined, reflecting both the chal-lenge of identifying new drug classes and a declining commit-ment to antibacterial drug discovery by the pharmaceuticalindustry (11, 42, 53, 63). The same period with a reduced rateof introduction of new agents has been accompanied by analarming increase in bacterial resistance to existing agents,resulting in the emergence of a serious threat to global publichealth (7, 9, 28, 39, 49, 60, 63, 64).The resistance problem demands that a renewed effort bemade to seek antibacterial agents effective against pathogenicbacteria resistant to current antibiotics. This minireview re-views the status of research in this critical therapeutic area. Wereevaluate the potential of older, unexploited agents and re-view current approaches to the discovery of new agents, in-cluding the identification of new molecular targets for antibi-otic action. Although other approaches such as the use ofvaccines, monoclonal antibodies, hematopoiesis-stimulatingfactors, and various immunoregulatory cytokines may prove tohave utility against infections caused by antibiotic-resistantbacteria (7), this minireview is limited to discussion of antibac-terial agents and strategies for the detection of new moleculartargets.