Our research in pharmacokinetic-pharmacodynamic [PK-PD] modeling focuses on mechanismbased models with excellent extrapolation and prediction properties. A key element is the explicit distinction between parameters for describing drug-specific and biological-system specific properties as determinants of the pharmacological response. Mechanism-based PK-PD models contain specific expressions for describing processes on the causal path between drug exposure and drug response. The different terms represent: target site distribution, target binding/activation, and transduction. Ultimately, mechanismbased PK-PD models will also describe the interaction with disease processes and disease progression. In increasing order of complexity our research focuses on the development of novel concepts of PK-PD modeling in: i] translational pharmacology [the prediction of efficacy- safety from preclinical tests], ii] developmental pharmacology [the prediction of variability in drug response in pediatrics], and iii] disease systems analysis [the prediction of drug effects on disease progression].