The intensity and time course of action of directly and reversibly acting drugs are related to and determined largely by the time course of drug and active drug metabolite concentrations in the body. When the pharmacokinetics and the concentration-effect relationship of a drug are known, it is often possible to predict the temporal pattern of its pharmacologic effect(s), including the maximum intensity and duration of action. Sites of action may not be immediately accessible to a drug even if it is injected intravenously; this may be reflected by a gradual increase in the intensity of effect despite decreasing drug concentrations in plasma, with maximum effects occurring later than maximum drug concentrations in plasma. Pharmacologic effects may persist well beyond the time when drug concentrations in plasma are no longer determinable; this is often caused by localization of the drug in an extravascular compartment. Drug distribution kinetics, pharmacologically active metabolites, and development of functional (as opposed to metabolic) tolerance may be responsible for time-dependent changes in drug concentration--pharmacologic effect relationships. Interindividual differences in patients' response to drug therapy may have a pharmacokinetic basis, a pharmacodynamic basis, or both. In clinical assessments of pharmacologic response, it is important to measure the therapeutically relevant effect, to determine interindividual and intraindividual variability, and to explore the possible influence of underlying diseases and other physiologic variables on drug concentration-effect relationships.