Classic pharmacokinetics (PK) rarely takes into account the full knowledge of physiology and biology of the human body. However, physiologically based PK (PBPK) is built mainly from drug-independent "system" information. PBPK is not a new concept, but it has shown a very rapid rise in recent years. This has been attributed to a greater connectivity to in vitro-in vivo extrapolation (IVIVE) techniques for predicting drug absorption, distribution, metabolism, and excretion (ADME) and their variability in humans. The marriage between PBPK and IVIVE under the overarching umbrella of "systems biology" has removed many constraints related to cutoff approaches on prediction of ADME. PBPK-IVIVE linked models have repeatedly shown their value in guiding decisions when predicting the effects of intrinsic and extrinsic factors on PK of drugs. A review of the achievements and shortcomings of the models might suggest better strategies in extending the success of PBPK-IVIVE to pharmacodynamics (PD) and drug safety.