Higher doses of renal replacement therapy have profound effects on pharmacotherapy, yet little research has been conducted in this area. High-volume renal replacement therapies influence both the pharmacokinetic and the pharmacodynamic profiles of all drugs administered to these critically ill patients. Intermittent high-dose "hybrid" hemodialysis therapies remove drugs to a much different degree than standard thrice-weekly hemodialysis, yet pharmacokinetic studies have not been performed in patients receiving these therapies. High-volume continuous renal replacement therapies offer dosing challenges not seen with standard low-dose therapies. This article describes the pharmacokinetic and pharmacodynamic issues presented by high-volume renal replacement therapies. Given the importance that pharmacotherapy has on optimal patient outcomes, a better understanding of the influence that high-volume renal replacement therapy has on drugs is essential if these high volume therapies are to be used successfully in the intensive care unit.