In vitro-in vivo extrapolation ((IVIVE) and empirical scaling factors (SF) of human intrinsic clearance (CL) were developed using one of the largest dataset of 455 compounds with data from human liver microsomes (HLM) and human hepatocytes (HHEP). For extended clearance classification system (ECCS) class 2/4 compounds, linear SFs (SF) are approximately 1, suggesting enzyme activities in HLM and HHEP are similar to those in vivo under physiological conditions. For ECCS class 1A/1B compounds, a unified set of SFs was developed for CL. These SFs contain both SF and an exponential SF (SF) of fraction unbound in plasma (f). The unified SFs for class 1A/1B eliminate the need to identify the transporters involved prior to clearance prediction. The underlying mechanisms of these SFs are not entirely clear at this point, but they serve practical purposes to reduce biases and increase prediction accuracy. Similar SFs have also been developed for preclinical species. For HLM-HHEP disconnect (HLM > HHEP) ECCS class 2/4 compounds that are mainly metabolized by cytochrome P450s/FMO, HLM significantly overpredicted in vivo CL, while HHEP slightly underpredicted and geometric mean of HLM and HHEP slightly overpredicted in vivo CL This observation is different than in rats, where rat liver microsomal CL correlates well with in vivo CL for compounds demonstrating permeability-limited metabolism. The good CL IVIVE developed using HLM and HHEP helps build confidence for prospective predictions of human clearance and supports the continued utilization of these assays to guide structure-activity relationships to improve metabolic stability.