The polymyxins (colistin and polymyxin B) are basic polypeptides that are bactericidal for certain gram-negative aerobic rods, including Pseudomonas. Because of poor distribution into tissues and substantial toxicity (primarily nephrotoxicity and neurotoxicity), systemic use of these agents has been limited to infections caused by multidrug-resistant gram-negative organisms that are sensitive only to the polymyxins. Colistin has been used with increasing frequency in the treatment of pan-resistant Acinetobacter baumanii and P aeruginosa and CRE infections. In the treatment of cancer patients with multidrug-resistant P aeruginosa, colistin has been found to be more effective than other antibacterial options. However, ceftazidime-avibactam is likely safer and more effective in the treatment of infection due to CRE. A number of issues limit the safe, effective use of the polymyxins, including confusion between polymyxin B and colistin, absence of pharmaceutical standards, uncertainties regarding susceptibility testing and breakpoints, pharmacokinetics in special patient populations, and the role of combination therapy. The confusion regarding dosing is underscored by the fact that the European dose recommendations differ substantially from those recommended by the FDA, particularly doses for patients with decreased kidney function. Experience suggests colistin is associated with less nephrotoxicity and neurotoxicity than previously described. Baseline renal impairment and older age strongly predict acute kidney injury; however, concomitant administration of ascorbic acid markedly reduces the risk of this complication. Higher doses of colistin are associated with increased microbiologic success and decreased 7-day mortality; however, they are also associated with worsened kidney function. While not associated with confirmed improved clinical outcomes, some clinicians recommend capping the dose at 9 million units/daily of colistin methanesulfonate and adding a second medication such as a carbapenem.