The brain is one of the most protected organs in the body. There are two key barriers that control the access of endogenous substances and xenobiotics (drugs or toxins) to the CNS. These physiological structures are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier. The BBB represents the main determinant of the effective delivery of drugs to the CNS. Good access through the BBB is essential if the target site is located within the CNS or, in contrast, can be a disadvantage if adverse reactions occur at central level. The development of new drugs targeted to the CNS requires a better knowledge of the factors affecting BBB permeation as well as in vitro and in silico predictive tools to optimize screening, and to reduce the attrition rate at later stages of drug development. This review discusses the particular characteristics of the biology and physiology of the BBB with respect to the permeation and distribution of drugs into the brain. The factors affecting rate, extent and distribution into the brain are discussed and a brief description of the in silico, in vitro, in situ and in vivo methods used to measure BBB transport are presented. Finally, the lastest proposals and strategies to enhance transport across the BBB of new CNS drugs are summarized.