The unique microenvironment within the central nervous system (CNS) relies upon the integrity of the blood-brain barrier (BBB). This selectively permeable barrier comprises interendothelial tight junctions located at the capillaries and postcapillary venules. Cells and structures in the local environment are required to maintain normal BBB function. When inflammation is present, the BBB itself plays an integral role in the inflammatory response by either producing or expressing a variety of cytokines, adhesion molecules, metalloproteinases, serine proteases, products of arachidonic acid metabolism, and nitric oxide. Understanding the role of the BBB during inflammation is essential when creating and employing a therapeutic regime for animals with CNS disease. This review focusses on recent discoveries about the BBB and its role in inflammation, and applies this knowledge to our current understanding of inflammatory CNS disease in dogs and cats.