Most drugs are given continuously. Clearance, the parameter which relates rate of elimination to drug concentration, is important because it defines the rate of administration required to maintain a plateau drug concentration. Together with the extent of distribution outside of plasma, clearance also determines the speed at which a drug is eliminated from the body. The sensitivity of organ clearance of a drug to changes in binding within blood depends on its unbound clearance. If unbound clearance is low, relative to organ blood flow, the extraction ratio (and clearance) will always be low and dependent on plasma binding. If the extraction ratio is high, elimination becomes perfusion rate-limited and clearance will be relatively insensitive to changes in binding, but oral bioavailability may exhibit dependence on binding if the liver is the major eliminating organ. A full insight into the implications of altered binding on pharmacokinetics requires a sound understanding of the physiology both of the eliminating organs and the distribution of drug within the body. Such information is steadily being acquired.