The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to avoid injury from external insults and toxins. Penetrating the blood-brain barrier (BBB) to achieve the drug concentrations required for efficacious target receptor occupancy in the brain region of interest is a unique and significant challenge facing medicinal chemists working on CNS targets. Prospective design of molecules with optimal brain exposure and safety profile requires in-depth understanding of the fundamental relationships between physicochemical properties and in vitro and in vivo outcomes. Following from the now widely accepted “rule of five” guidelines for the design of oral drugs, the physicochemical properties for brain penetration have been extensively studied in an effort to define the characteristics of successful CNS drug candidates. Several key physicochemical properties have been identified that influence the rate of brain permeability and extent of brain penetration, including H-bonding potential, molecular weight, lipophilicity, polar surface area (PSA), ionization state and rotatable bond count. The ability to process this information effectively and engage in multi-parameter prospective design ultimately determines the success in delivering high-quality drug candidates that are suitable robustly to test hypotheses in the clinic and have good probability of reaching the market. This chapter focuses on the medicinal chemistry aspects of drug candidate optimization particular to the CNS therapeutic area, such as crossing the blood-brain barrier (BBB), as well as safety-related issues frequently challenging CNS programs such as hERG selectivity and phospholipidosis.