In spite of an impressive increase in CNS drug discovery, the biggest obstacle remains the effective delivery of these agents across the blood brain barrier, hence the delivery of therapeutic agents to the brain is limited by the presence of the Blood-Brain Barrier (BBB). In the basic science of brain physiology and disease in the past decade, delivery issues have received minimal attention. Current estimates are that 98% of all small molecule drugs minimally cross the BBB, and negligible amounts of large molecule drugs cross the BBB, except leakage in areas of BBB dysfunction. Lipid soluble drugs with a molecular weight under 400-600 daltons are transported to through a blood-brain barrier by lipid mediated transport. This hindrance has slowed the application of pharmacotherapy and immunotherapy in brain diseases. Hence it is important to unite brain targeted drug discovery and CNS drug delivery as early as possible for CNS drug development process. In this report we review the major advances in brain drug targeting research, including approaches to circumvent the BBB for brain delivery by making use of endogenous transport mechanisms or bypassing the BBB altogether. Among all the approaches used for increasing brain delivery of drugs, the most accepted method is the use of the physiological approach. The physiological approach use specific receptors already expressed on the capillary endothelial cells forming the BBB and necessary for the survival of brain cells. This review intends to detail the recent advances in the field of brain-targeting and drug delivery to CNS.