Abstract: Blood-brain barrier is a natural protection for human body.It protects central nervous systemfrom the interruption and damage of xenobiotics.However, it prevents potential drugs aimed at central nervous system, thus becomes an obstruction for the development of central nervous system drugs.The recent development of blood-brain barrier permeability research and several lead optimization strategies to improve blood-brain barrier permeability are reviewed.These structure optimization methods include increasinglipophilicity, reducing hydrogen bond doners, simplifying molecule, increasing rigidity, lowering polar surface area, avoiding acid group, prodrug strategy, modifying into active transporter's substrates, as well as avoiding P-glycoprotein recognized structures.