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 is used for pan-resistant Acinetobacter baumanii and P aeruginosa and CRE infections. However, safer alternatives are available; ceftolozane-tazobactam is clinically effective against multidrug-resistant P aeruginosa with fewer toxicities, and ceftazidime-avibactam is safer and more effective in the treatment of infection caused by CRE. Meropenem-vaborbactam is likely more effective and certainly less toxic than colistin. 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. Baseline renal impairment and older age strongly predict acute kidney injury. 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.