The success rate to achieve clinical approval of drugs developed to treat diseases of the central nervous system (CNS) is the lowest of all disease indications. A large contributor to this poor success rate is failure of small molecules to pass through the blood-brain barrier (BBB), a barrier composed of capillary endothelial cells connected by tight junctions that functions to extrude xenobiotics from the brain. Designing small molecules to be BBB penetrant has been the subject of intensive research and has resulted in a series of guidelines to attain the best possible chances of BBB penetration. This review will analyze the current state of thinking in ranking the importance of various physicochemical properties required to select BBB penetrant molecules, describe model systems to determine BBB penetration, summarize data analysis methods and provide an outlook on further developments in the field.