Human liver microsomal intrinsic clearance has become a commonly measured parameter during drug discovery, and such data are used to design compounds predicted to possess optimal drug disposition characteristics. Liver microsomal intrinsic clearance values can be scaled and used to predict hepatic clearance in humans. Clearance, when combined with the volume of distribution, determines the half-life of a drug. Hepatic clearance, when combined with absorption, determines the oral bioavailability of a drug. Half-life and oral bioavailability are key determinants of the dosing regimen, i.e., size of dose and frequency of administration. Thus, the accurate prediction of human clearance is important in the selection of new compounds for progression into development, as new drugs on the market must not only be efficacious and safe, but must also be convenient to use for patients and physicians. Over the past decade, exploring methods whereby human clearance can be predicted from in vitro data has been an area of active research in drug metabolism science. Human liver microsomes have been a key tool in this research. This in vitro system possesses many of the major drug metabolizing enzymes and is thus applicable to a wide variety of compounds. This review describes the theoretical and practical aspects of predicting clearance from human liver microsomal intrinsic clearance data, a summary of advantages and shortcomings of this in vitro system, a synopsis of recent applications of human liver microsomal intrinsic clearance data in clearance predictions, and a discussion of potential future directions for this field.