With increasing life expectancy, brain-related diseases have become a major health problem globally. The human brain contains on the order of 100 million capillaries containing a surface area of ≈12 m2. Nearly every neuron in the brain has its own capillary, with an average distance from capillary to neuron of 8–20 μm. Different approaches have been developed to improve drug delivery across the BBB. These encompasses the use of nanoparticles, brain permeability enhancers, exosome and other means as described elsewhere. Among the these novel delivery systems, peptide-based drug delivery afford a good degree of selectivity and significant enhancement of drug bioavailability/efficiency at the target site. Two clearly differentiated routes, namely passive diffusion (i.e. lipophilic pathway) and active transport (mainly, adsorptive- or receptor-mediated transcytosis, AMT and RMT, respectively), are the most suitable approaches for drug delivery to the brain. The former is conveniently used for small cargos, while the latter enables the delivery of large therapeutics, such as proteins and nanoparticles (NPs). Compounds that are lipophilic, neutral or uncharged at pH 7.4 and have less than 8 hydrogen bonding groups are more suitable to cross the BBB. Several receptors present in the BBB, including transferrin, the insulin receptor, and the low-density lipoprotein receptor (LDLR), are known to allow the passage of cognate protein ligands into the brain. Low-density lipoprotein receptor-related protein-1 (LRP-1) is highly expressed in brain endothelial cells as well as brain tumour cells, neurons and astrocytes; it is also expressed in the lung, ovary, uterus and liver. The nicotinic acetylcholine receptor (nAChR) is widely expressed in the brain, including the endothelial cells of brain capillaries. The human transferrin receptor (TfR), highly expressed in brain capillaries, mediates the delivery of iron to the brain. TfR is also expressed in choroid plexus epithelial cells and neurons.