The blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) represent the main interfaces between the central nervous system (CNS) and the peripheral circulation. Drug exposure to the CNS is dependent on a variety of factors, including the physical barrier presented by the BBB and the BCSFB and the affinity of the substrate for specific transport systems located at both of these interfaces. It is the aggregate effect of these factors that ultimately determines the total CNS exposure, and thus pharmacological efficacy, of a drug or drug candidate. This review discusses the anatomical and biochemical barriers presented to solute access to the CNS. In particular, the important role played by various efflux transporters in the overall barrier function is considered in detail, as current literature suggests that efflux transport likely represents a key determinant of overall CNS exposure for many substrates. Finally, it is important to consider not only the net delivery of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Potential approaches to increasing both net CNS and target-site exposure, when such exposure is dictated by efflux transport, are considered.