The significance of the total body clearance (CL) is studied based on a physiological pharmacokinetic model. In the absence of evidence to the contrary, and for the sake of uniformity, it is proposed that the elimination rate of a drug at any time after various routes of dosing be assumed to be proportional to its systemic arterial plasma (blood) concentration with a proportionality constant equal to CL. The CL, calculated by the intravenous dose divided by the AUC, is defined as the hypothetical volume of the systemic arterial plasma (blood) completely cleared of drug per unit time even though the drug is eliminated by the lungs and venous plasma is assayed. A marked difference in the calculated elimination rate of lidocaine in patients based on arterial or venous plasma data is demonstrated. The calculated CLs which are sometimes greater than the cardiac output can be rationalized. The limitation of conventional multicompartmental mammillary modelling theory in the defining of CL is discussed.