Polymyxin B and colistin are being used increasingly for the treatment of infections caused by gram-negative bacteria that are resistant to all other currently available antibiotics. Although the polymyxins have been available in the clinic for around 50 years, they have never been subjected to the drug development procedures required of modern pharmaceuticals. As a result, the available knowledge on the pharmacokinetics (PK), pharmacodynamics (PD), and toxicodynamics (TD) of the polymyxins is limited. Although significant advances have been made in the last 5 years or so, there are still large gaps in our understanding of the PK, PD, and TD, and of the PK/PD and PK/TD relationships. This information is required to generate recommendations on dosage regimens for various categories of critically ill patients. This paper reviews the growing understanding of the pharmacology of the polymyxins and factors that may impact on the optimization of the dose of these antibiotics in critically ill patients.