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Drug delivery to the central nervous system (CNS) remains a challenging area of investigation both for clinical and basic neuroscientists. We review the current understanding of the morphology and physiology of the blood-brain barrier (BBB), the pharmacological parameters that determine drug penetration into the CNS, and the spectrum of strategies used to improve drug delivery to the brain and spinal cord. Cerebral capillary endothelial cells can be distinguished from endothelial cells in other tissues by the increased number of mitochondria, paucity of pinocytic vesicles, and presence of occlusive intercellular tight junctions and a glial sheath around the capillary. Drug delivery to the CNS is primarily determined by the blood-brain barrier, but also depends on the blood-cerebrospinal fluid (CSF) barrier and on the CSF-brain barrier. The physicochemical properties of drugs that determine access into the CNS include molecular size, molecular complexity, bioavailability, lipid solubility, ionization, and molecular recognition by membrane-based facilitative and active transporters. Current strategies for improving drug delivery to the brain fall into three categories: (a) drug modification, (b) blood-brain barrier modification, and (c) alternative routes for drug delivery. The most successful techniques for drug modification have been those involved in the design of lipophilic analogues, prodrugs, and carrier-mediated drugs. BBB modification has been accomplished through transient osmotic opening of the cerebral capillary endothelium. Alternative routes for drug delivery include intraarterial, intraventricular, intrathecal, and interstitial administration of agents into the CNS. Interstitial administration of drugs into the brain can be accomplished using either catheters or controlled release polymeric matrices. A wide range of rational strategies for drug delivery to the CNS has been developed in the 25 years since the site of the BBB was identified, and many other advances are anticipated in the near future.