A number of experimental observations in the late 1960s, early 1970s could not be explained by the pharmacokinetic theory available at that time. For example rats receiving phenobarbital as an enzyme inducing agent exhibited increased elimination of phenylbutazone in vitro in liver microsomes and in vivo in whole animals compared to that observed in non-induced animals. However, for desipramine, although phenobarbital increased elimination in microsomes, no change in plasma disappearance was noted in vivo for this drug between rats induced with phenobarbital and control rats. Similar in vitro–in vivo discordancies were seen with changes in protein binding. The introduction of clearance concepts in the early 1970s by Professor Rowland and others provided the scientific rationale for these apparently contradictory findings and the recognition that clearance, not half-life, was the measure of the body’s ability to eliminate drugs and most importantly that changes in pathology and physiology could be correlated with measures of clearance. Up to that time half-life was well recognized in terms of basic chemical principles as an appropriate measure of the rate of elimination and reflective of changes in the rate of elimination. The difference between chemistry and pharmacokinetics, however, is that in chemistry the volume in which the reaction occurs does not change. In contrast, in pharmacokinetics, disease states and differences in physiology can change the space available in which the drug may distribute in the body. Thus, it was necessary to develop a pharmacokinetic measure of volume that was independent of elimination, i.e., Vss. Now, the relationship between Vss and clearance led to a unique measure of time of drug in the body, the mean residence time. Although this parameter is calculated in all PK programs, very few pharmaceutical scientists know how it can be useful. Very recently, we have shown that the concepts of accumulation, prediction of which is the clinically relevant use for half-life and mean residence time, are flawed and that the appropriate time dependent parameter to predict accumulation has not been previously correctly identified. Finally, when clearance concepts were developed our understanding of the importance of drug transporters was nonexistent. A critical, and generally unrecognized assumption (which is only explicitly stated in Professor Rowland’s seminal 1973 paper), in the development of the theory of clearance is that the unbound drug concentration in the organ of elimination is in a constant equilibrium with the unbound drug concentration in the systemic circulation, where drug concentration measurements are made. Transporter drug–drug and disease interactions may, in fact, change this equilibrium and potentially what we consider as intrinsic clearance, may not be independent of an eliminating organ volume parameter, contrary to what we have been teaching for the past 37 years.