Corticosteroids are an important and often life-saving class of drugs. Despite a broad array of serious potential side effects, such as glaucoma, hypertension, hyperglycemia, Cortisol suppression, osteoporosis, and peptic ulcers, corticosteroids provide an effective first-line therapeutic choice for conditions that require immunosuppressive agents. Studies evaluating the mode of action revealed that corticosteroids achieve their activity mainly via interactions with specific receptors. 1,2 Recently, however, additional mechanisms of action have been proposed. 3,4 “Direct” and “gene-mediated” effects can be distinguished by the absence or presence of a delayed onset. The increased understanding of drug action has not translated into designing optimal dosage regimens. Dosing for different therapeutic requirements is usually determined empirically and is subject to considerable debate. A new approach for solving this dilemma is the use of pharmacokinetic-pharmacodynamic (PK-PD) modeling to optimize therapeutic outcomes. Recently, major advances were made in the development of appropriate corticosteroid models. The models consider both pharmacokinetics and mechanism of action to predict therapeutic profile. Therefore, it is the aim of this chapter to provide an introduction to different PK-PD models, their clinical relevance, and applications. Important pharmacokinetic and pharmacodynamic parameters will be considered briefly.