Development of new chemical entities is costly, time-consuming, and has a low success rate. Accurate prediction of pharmacokinetic properties is critical to progress compounds with favorable drug-like characteristics in lead optimization. Of particular importance is the prediction of hepatic clearance, which determines drug exposure and contributes to projection of dose, half-life, and bioavailability. The most commonly employed methodology to predict hepatic clearance is termed to extrapolation (IVIVE) that involves measuring drug metabolism , scaling-up this intrinsic clearance to a prediction of intrinsic clearance by reconciling the enzymatic content between the incubation and an average human liver, and applying a model of hepatic disposition to account for limitations of protein binding and blood flow to predict clearance. This manuscript reviews common techniques used to predict hepatic clearance as well as current challenges and recent theoretical advancements in IVIVE.