Development of resistance to antibiotics used for human therapy is a persistent problem and has always been the basis for the continuous efforts of drug companies to produce novel agents. A variety of approaches taken in industry over the past quarter-century, from screening to computer-assisted design to the use of genomics to generate new leads that can be taken through pharmacological testing, will be reviewed, citing examples. Non-traditional approaches, including the screening for agents that affect bacterial virulence will also be described.