The movement of lymphocytes from the microvasculature into the central nervous system (CNS) parenchyma is an essential step in the pathogenesis of a variety of infectious and autoimmune neuroinflammatory diseases. The lymphocyte chemoattractant CXCL10 and its receptor, CXCR3, are expressed by the CNS and by CNS infiltrating lymphocytes, respectively, only in patients with ongoing CNS inflammation, suggesting an important role for these molecules in the pathogenic process. Numerous studies utilizing animal models and transgenic approaches have indeed supported a role for CXCL10 in the intraparenchymal trafficking of lymphocytes during acute CNS inflammation; however, other studies suggest that its expression is not required for the development of autoimmune forms of CNS inflammation and, in fact, that interference with CXCL10 signaling could lead to increased neuroinflammation. This review will consider the data from these studies and attempt to reconcile them through comparisons of both the neuroinflammatory models and the effects of CXCL10 in the CNS versus lymphoid tissues. Finally, it will define directions for future analyses of CXCL10 and CXCR3 in CNS inflammation so that their potential therapeutic utility can be more completely determined. © 2004 Wiley‐Liss, Inc.