Cytokines and chemokines are potent biologic response molecules that play a key role in cellular communication in physiologic and pathophysiologic states. An understanding of the actions and roles of these molecules in CNS biology has been greatly facilitated by molecular genetic approaches that permit the targeted manipulation of gene expression in an intact organism. Studies in promoter-driven transgenic mice with CNS production of a number of cytokines or chemokines have demonstrated that these factors can directly induce a spectrum of cellular alterations often resulting in pronounced neurological disease (Table 1). Thus, these factors, in addition to initiating and maintaining immunoinflammatory responses, can be direct mediators of CNS injury. The neuropathological outcomes in the transgenic mice often recapitulate those reported in human neurological disorders such as MS, neurological diseases associated with AIDS and Alzheimer's disease, pointing to the importance of these animal models to our understanding of the role of cytokines and chemokines in these human disorders. Despite problems of timing and tissue specificity as well as some inconsistencies in the findings from different groups, knockout mice have begun to provide insights that are altering our view of the contribution made by individual cytokines to immunoinflammatory responses in the brain. For example, IL-6 and TNF were originally viewed as having minor and major proinflammatory contributions, respectively, in EAE, but now, based on findings from knockout mice, the opposite seems true. Studies in transgenic and knockout mice now offer strong evidence that, in addition to being mediators of damage, cytokines can have beneficial functions, e.g. the antiviral functions of the IFNs or the trophic and/or neuroprotective actions of some cytokines such as IL-6 and TNF. Clearly, studies in mutant mice, as summarized here, will continue to provide important insights into the nature of cytokine and chemokine actions in the CNS and will offer the possibility that we may identify new targets for effective therapeutic intervention in neuroinflammatory disorders.