There is a growing momentum to use in vitro methods, nestled in in silico physiologically based pharmacokinetic models as the primary source of prediction of human clearance. This represents a shift in the paradigm for predictions in humans, which has been traditionally based on in vivo empirical approaches involving allometric scaling. For hepatic clearance of lipophilic metabolised compounds, methodology for scaling based on in vitro data is well established and approaches based on in vitro data alone seem to be the most accurate. However, limitations in in vitro methods exist for compounds cleared by other mechanisms, such as those for which active transport is a major determinant of the hepatobiliary and renal elimination processes. A major challenge for any clearance prediction is the assessment of variability and uncertainty. Integrative and mechanistic approaches such as physiologically based scaling provide the most promising way of dealing with these aspects. In this review, the authors assess advances in in vitro methods for hepatic and renal clearance predictions with particular emphasis on mechanistic approaches.