Critically ill patients with severe infections often have altered pharmacokinetic and pharmacodynamic variables that lead to challenging treatment decisions. These altered variables can often lead to inadequate dosing and poor treatment outcomes. The pharmacokinetic parameters include absorption, distribution, metabolism, and excretion. Pharmacodynamics is the relationship between drug serum concentrations and pharmacologic and toxicologic properties of the medication. In addition to these altered parameters, these critically ill patients frequently are receiving organ support in the forms of continuous renal replacement therapy or extra-corporeal membrane oxygenation. Altered pharmacodynamics can lead to decreased end-organ perfusion, which can ultimately lead to treatment failure or exposure-related toxicity. The most common antimicrobials utilized in the intensive care unit are classified by the pharmacodynamic principles of time-dependent, concentration-dependent, and concentration dependent with time-dependence. Thus, the aim of this review is to outline pharmacokinetic and pharmacodynamic changes of critically ill patients with severe infections and provide strategies for optimal antibiotic agent dosing in these patients.