The polymyxins—colistin and polymyxin B—are an increasingly important part of the antimicrobial arsenal given the rising rate of infections due to multidrug-resistant gram-negative bacteria. Although the drugs have available since the 1950s, only recently have pharmacokinetic and pharmacodynamic data been available to guide appropriate use of these drugs. Far more data and global clinical experience exist for colistin, available as the prodrug colistimethate sodium (CMS), compared with polymyxin B. Concerns raised about variability in the ability to achieve therapeutic drug concentrations when dosing CMS have led many clinicians to desire a more pharmacokinetically reliable product. The pharmacokinetic and pharmacodynamic advantages of polymyxin B compared with CMS are compelling, but clinical experience has not consistently corroborated these data. Prospective, comparative data evaluating both drugs in combination with other antimicrobials as well as comparing polymyxin B and CMS directly will inform optimal use of each drug. Some of these investigations are currently under way. In the meantime, based on current data, both drugs appear to be appropriate for use in the clinical setting.