The vascular endothelial cells (ECs) that separate the bloodstream from the brain interior are so impermeable that the brain vasculature is often referred to as the blood–brain barrier (BBB). As a result of its barrier properties, the BBB plays an extremely important role in central nervous system (CNS) homeostasis by protecting neurons from fluctuations in blood composition and from toxic blood-borne substances. Except for small regions of the brain, the barrier properties are found throughout the entire brain and include capillaries, arterioles, and venules as well as larger arteries and veins. As the vessels advance from the meningeal membranes that envelop the brain and into the brain matter, vascular permeability decreases rapidly and barrier-like impermeability arises. Although the BBB permeability for many substances is highly restricted, a multiplicity of molecular transport systems exist to provide the brain with necessary nutrients. The same barrier function that is critical for normal brain function also provides a formidable hurdle for delivery of therapeutics to the brain under conditions of neurological disease.

Although the endothelium provides the barrier properties of the BBB, it is the local brain microenvironment that elicits the unique phenotype. Vascular smooth muscle cells line precapillary arterioles, pericytes share a basement membrane with capillary ECs, astrocytes ensheathe the microvessels, and nerve terminals contact the endothelium. Together with the endothelium, these perivascular cell types constitute the so-called neurovascular unit. In this chapter, we review the microenvironmental cues that function in BBB maintenance, describe the BBB phenotype in detail, and highlight the role for the BBB in brain diseases such as stroke, multiple sclerosis (MS), and cerebral malaria.