“We know everything about antibiotics except how much to give,” Maxwell Finland once stated. Finally, with the proliferation of pharmacodynamics as a science, we are addressing the question of how much to give. We have moved from an era of more or less arbitrary antimicrobial dosage selection toward one characterized by evidence-based optimal dosing strategies. Optimizing antimicrobial therapy in critically ill patients is more than just the selection of a suitable dose for a particular patient. Optimizing therapy also involves the selection of an appropriate single or combination antibiotic regimen that is active against the suspected or documented pathogens at the site(s) of infection. The regimen should offer the fewest potential adverse events, and the duration of therapy should be the shortest possible so as not to encourage resistance. Dosing of the chosen regimen should reflect variables that are often ignored, such as the patient's weight and age. The new continuous renal replacement therapies are commonly used in the critical care unit and must be considered. Finally, the cost of the regimen should be considered, but not only the cost to purchase the chosen antimicrobial agent but the cost to administer it (ie, the cost of minibags or syringes, intravenous tubing, saline flushes [all multiplied by the number of times per day the drug is given]), and, most importantly, if the patient fails to respond to therapy, the cost necessary to re-treat the patient to bring about a cure. In this review, we discuss some of the principles required to optimize antimicrobial dosing and recently obtained data regarding its application to the critically ill patient.