This review describes specific strategies for targeting to the central nervoussystem (CNS). Systemically administered drugs can reach the brain by crossing one of twophysiological barriers resistant to free diffusion of most molecules from blood to CNS: theendothelial blood-brain barrier or the epithelial blood-cerebrospinal fluid barrier. Thesetissues constitute both transport and enzymatic barriers. The most common strategy fordesigning effective prodrugs relies on the increase of parent drug lipophilicity. However,increasing lipophilicity without a concomitant increase in rate and selectivity of prodrugbioconversion in the brain will result in failure. In these regards, consideration of theenzymes present in brain tissue and in the barriers is essential for a successful approach.Nasal administration of lipophilic prodrugs can be a promising alternative non-invasiveroute to improve brain targeting of the parent drugs due to fast absorption and rapid onsetof drug action. The carrier-mediated absorption of drugs and prodrugs across epithelial andendothelial barriers is emerging as another novel trend in biotherapeutics. Several specifictransporters have been identified in boundary tissues between blood and CNScompartments. Some of them are involved in the active supply of nutrients and have been used to explore prodrug approaches with improved brain delivery. The feasibility of CNSuptake of appropriately designed prodrugs via these transporters is described in detail.