Over the years, there has been an increase in the number and quality of available in vitro tools for the assessment of clearance. Complexity of data analysis and modelling of corresponding in vitro data has increased in an analogous manner, in particular for the simultaneous characterization of transporter and metabolism kinetics, together with intracellular binding and passive diffusion. In the current chapter, the impact of different factors on the in vitro-in vivo extrapolation of clearance will be addressed in a stepwise manner, from the selection of the most adequate in vitro system and experimental design/condition to the corresponding modelling of data generated. The application of static or physiologically based pharmacokinetic models in the prediction of clearance will be discussed, highlighting limitations and current challenges of some of the approaches. Particular focus will be on the ability of in vitro and in silico predictive tools to overcome the trend of clearance underprediction. Improvements made as a result of inclusion of extrahepatic metabolism and consideration of transporter-metabolism interplay across different organs will be discussed.