The capillary endothelium of the brain and spinal cord possesses tight junctions and, thus, behaves as a continuous lipid bilayer that prevents the passage of highly polar and lipid-insoluble substances. Highly active enzymes expressed in the brain endothelial cells and cerebral pericytes also represent a metabolic component that contributes to the homeostatic balance of the central nervous system (CNS). Peptides cannot enter the brain and spinal cord from the circulating blood because they are highly polar and lipid insoluble, metabolically unstable, and generally do not have active transport systems in this membranous barrier. Hence, the blood-brain barrier (BBB) is the major obstacle to peptide-based therapeutics that are potentially useful for combating diseases affecting the central nervous system. The article discusses invasive, physiological-based and chemical-enzymatic approaches to overcome the BBB by reviewing both primary and patent literature.