The seminal paper on the liver physiologically-based pharmacokinetic (PBPK) model by Rowland et al. (J Pharmacokinet Biopharm 1:123-136, 1973) that described the influence of blood flow, intrinsic clearance, and binding on hepatic clearance had inspired further development of PBPK modeling of the liver, kidney and intestine as well as whole body. Shortly thereafter, a series of papers from Pang and Rowland compared the well-stirred and parallel-tube liver models and sparked further development on clearance concepts in the liver, including those described by the dispersion model. From 2005 onwards, several seminal papers by Rodgers and Rowland, in their recognition of the binding of molecules to tissue acidic and neutral phospholipids, improved the methodology in providing estimates of the tissue-to-plasma coefficient and rendering easy calculation of these hard-to-get constants. The improvement has strongly consolidated the basic premise on PBPK modeling and simulations and these basics have allowed scientists to focus on other important variables: membrane barriers, and transporter and enzyme and their heterogeneities that further impact drug disposition. In particular, the PBPK models have delved into sequential metabolism and futile cycling to illustrate how transporters and enzymes could affect the metabolism of drugs and metabolites. PBPK models that are especially pertinent to metabolite kinetics are being utilized in drug studies and risk assessment. These types of PBPK modeling reveal differences in kinetics between the formed vs. preformed metabolite, showing special considerations for membrane barriers, and the influence of competing pathways and competing organs.