The large surface area and the short diffusion distance from capillaries of the blood brain barrier (BBB) to the neurons facilitate the drugs and nutrients access to the brain. Penetration of chemicals to the BBB occurs using a combination of intra and intercellular passages. Tight junctions regulate the intracellular passage of molecules according to their physicochemical properties (e.g. lipophilicity, ionisation and polarity), where inter cellular penetration is regulated by influx and efflux transporters, endocytosis and passive diffusion. Poor pharmacokinetic properties (absorption, distribution, metabolism and excretion) and toxicity are responsible for most of the failures in drug discovery projects. This problem is more evident for CNS drugs because of the restrict barrier function of blood brain barrier. The CNS drug discovery attracted more attentions since the diseases pattern has been changed during recent decades and aging disorders are one of the major health problems. Drug exposure is controlled by plasma pharmacokinetic properties of drug which are different from brain pharmacokinetic and can be studied using common pharmacokinetic studies, where BBB permeability depends on physicochemical properties of drug compound and physiologic function of the BBB (physical barrier, transport, metabolic, ...) and need special study techniques. In this chapter, fundamentals of BBB, permeation mechanisms, penetration measurement methods and penetration prediction methods are discussed.