Accumulating evidence shows that adhesion molecules are critically involved in inflammatory demyelination in the focusing of systemic immune responses into the target tissue, the nervous system.Adhesion molecules are upregulated through the action of cytokines. Tumor necrosis factor alpha appears to be of prime importance. Circulating adhesion molecules probably reflect acute inflammatory episodes in the central and peripheral nervous system, but may also function to modulate ongoing inflammatory responses. Cytokines released by TH 1 cells render resident and immigrant macrophages, as well as microglia, activated to synthesize and release increased amounts of inflammatory mediators, such as oxygen radicals, nitric oxide metabolites, and components of the complement system. A more detailed understanding of the sequence of immunopathologic events that culminate in myelin damage in the central and peripheral nervous systems has revealed several sites to which more specific and effective immunointervention can be targeted. © 1995 American Academy of Neurology.