1. Drugs that target the central nervous system (CNS) are under-represented in the pharmacopoeia because of the difficulties of overcoming passive and active defences of the blood-brain barrier (BBB). Methods have been developed in drug discovery to make decisions about whether a compound crosses the BBB. Less is known about how the rate and extent of CNS penetration of a drug affects its clinical behaviour, largely because of past difficulties in measuring the cerebral uptake of drugs in humans. Three methods for doing so are reviewed. 2. Microdialysis is sometimes used as a clinical tool for monitoring the brain in neurointensive care and opportunistic pharmacological studies are possible. The method is relatively cheap and simple, measures free drug concentrations and is better suited to characterizing slowly changing brain drug concentrations. 3. Measuring cerebral drug uptake using positron emission tomography imaging requires the use of short-lived isotopes (labelled drug or labelled receptor ligand). Data with high spatial and temporal resolution can be collected, but the method requires expensive infrastructure. 4. Jugular bulb catheters collect pure brain venous blood and are sometimes placed for neuromonitoring. Cerebral drug uptake is inferred from the arterial to cerebral venous concentration difference. The method is relatively cheap and simple and allows global brain concentrations to be estimated. It is better suited to characterizing rapidly changing brain concentrations and effects. 5. The cerebral kinetics of a cerebro-active drug can make substantial contributions to its clinical behaviour. For example, loperamide is a peripherally acting opioid that has little CNS effect due to the active efflux transport of loperamide from the brain back into the blood by transporters including P-glycoprotein. The opioids alfentanil and fentanyl differ in their duration of action largely because of differences in their cerebral distribution volume rather than differences in systemic kinetics. The onset of anaesthesia of the intravenous anaesthetic propofol is governed almost completely by the kinetics of the first-pass passage of the drug through the brain and is more affected by changes in cerebral blood flow than hepatic clearance. 6. Continuing to exploit and develop these methods may provide new avenues to enhance the safety and efficacy of cerebro-active drugs in clinical practice.