Antibiotic resistance has evolved over 60 years from a merely microbiological curiosity to a serious medical problem in hospitals. Resistance has been reported in almost all species of bacteria to various classes of antimicrobial agents including recently evaluated ones. Bacteria regulated resistance by different mechanisms. Inappropriate use of an antimicrobial agent selects resistant strains much more frequently. Since it is not expected that some epoch-making new antimicrobial agents will be developed in the near future, proper use of existing antimicrobial agents which is based on the mechanisms of action of antimicrobial agents and of resistance of bacteria, and of control of nosocomial infection are very important to reduce the further spread of resistant bacteria. With the search for natural sources of new antimicrobial substances now appearing frustrated, the genomic approach in the 21st century may be the only fruitful way to develop truly novel chemotherapeutic agents against bacterial diseases.