For a long time, the central nervous system (CNS) was considered an immunological privileged site, where the highly specialized endothelial cells of the blood-brain barrier restrict the trafficking of immune cells into the brain. However, inflammation in the CNS can still occur and the brain itself may become a site of inflammation by responding to nonself antigens (such as bacteria or viruses) or self-antigens. Under these inflammatory conditions, mononuclear cells infiltrate the CNS and mediate the immune response further. One of the most common and severe inflammatory disorders of the CNS is the demyelinating disease multiple sclerosis (MS), which is characterized by multiple sclerotic lesions in the brain, brain stem, and spinal cord. These perivascular centers of inflammation become active or less active during the course of the disease and the formation of new lesions seems to be a continuous process. This chapter focuses on the initial cellular events underlying new MS lesion formation, with an emphasis on the role of monocyte- derived macrophages and on the blood-brain barrier as a site of entry for inflammatory cells during the process of lesion formation in the course of the disease.