Cytokines are potent biological response modifiers that exhibit a spectrum of cellular actions. These factors have been implicated as important mediators of physiologic and possibly pathophysiologic processes within the CNS. Targeting the expression of cytokines to specific tissues in transgenic mice has provided a powerful approach to the investigation of complex cellular responses at a localized level and also recapitulated more closely the expression of these mediators as found in pathogenetic processes. This review will focus on the recent application of transgenic technology to achieve the specific cerebral expression of cytokines. The targeting of cytokine gene expression to astrocytes in transgenic mice has provided new and dramatic insights into the CNS pathobiology of these host-response molecules. Specifically: (1) transgenic expression of the cytokines IL-6, IL-3 and IFN-alpha in the CNS results in the development of acute (high expression) or chronic progressive (low expression) CNS disease associated with a spectrum of clinical, physiologic and pathologic manifestations; (2) although the clinical, cellular and molecular phenotype produced by the cerebral expression of the various cytokines showed some overlap, the differences were more prominent reflecting the unique actions of each cytokine; (3) these transgenic models which recapitulate many of the structural and functional impairments seen in human neurodegenerative diseases, highlight the point that cytokines, which normally function as primary regulators of the host response, also have the potential to mediate significant injury in the CNS. Therefore, these transgenic models have provided a valuable tool for advancing our understanding of the CNS pathobiology of cytokines and will no doubt offer a unique resource for the development and testing of therapies aimed at abrogating the toxic actions of these important mediators.