The microvasculature of the central nervous system (CNS) is characterized by tight junctions between the endothelial cells and, thus, behaves as a continuous lipid bilayer that prevents the passage of polar and lipid-insoluble substances such as peptides. Highly active enzymes expressed in the morphological components of the microcirculation also represent a metabolic component that contributes to the homeostatic balance of the CNS. Peptides generally cannot enter the brain and spinal cord from the circulating blood because they are highly polar and lipid insoluble, metabolically unstable, and active transport systems only exist for very few of them in this membraneous barrier separating the systemic circulation from the interstitial fluid of the CNS. This blood-brain barrier is, therefore, the major obstacle to peptide-based drugs that are potentially useful for combating diseases affecting the brain and spinal cord. This review discusses and critically evaluates invasive, chemical-enzymatic (prodrug and chemical delivery/targeting system) and biological carrier-based approaches to overcome the blood-brain barrier for these highly active and versatile molecules that are very attractive as a future generation of neuropharmaceuticals.