In the discovery and development of new medicines, the ability to accurately predict human pharmacokinetic (PK) properties is a critical part of the translational R&D process, enabling (i) differentiation of clinical candidates, (ii) facilitating first-in-human studies, (iii) projection of efficacious dose regimens (dose size and frequency), and (iv) insight into safety margins. A wide range of approaches have been developed, proposed, and qualified over many years to predict the fundamental PK parameters, clearance, volume of distribution, oral absorption, and bioavailability. The focus of this chapter is on one of the more challenging PK properties to predict in human, drug clearance (CL), which is integral to understanding whether a compound will have an adequate half-life and oral bioavailability to support safe and efficacious therapy. Drug clearance is a proportionality constant between the rate of elimination from the body (systemic clearance) or an organ (organ clearance) and its concentration at the site of measurement, i.e. blood or plasma. A physiologically more meaningful definition is the apparent volume of blood (or plasma or plasma water) cleared of drug per unit time and can be expressed as blood CL, plasma CL, or unbound CL, respectively, as well as in terms of systemic (total body) CL or specific organ CL. The major pathways of elimination for most drugs are hepatic metabolism, biliary excretion, and renal excretion.