The brain is not directly accessible for intravenously administered macro- and most small molecular drugs because of the presence of the blood-brain barrier (BBB). In this respect the BBB functions as a physical and metabolic barrier which is presented by the endothelial cells in brain capillaries. In order to overcome the BBB, therapeutic compounds have been targeted to internalizing receptors at the BBB. In this review we summarize the different approaches that have been described in current literature, including the possible difficulties for clinical application. Particularly, we focus on the possible impact of brain diseases on receptor-mediated transport to the BBB/brain and how this may affect various targeting strategies. Moreover, it is our opinion that a differential drug targeting/delivery approach should be applied to treat central nervous system (CNS) diseases that are related to the BBB alone, and for CNS diseases that are related to both the brain and the BBB.