Interleukins 1α and 1β (IL‐1) are very potent signaling molecules that are expressed normally at low levels, but are induced rapidly in response to local or peripheral insults. IL‐1 coordinates systemic host defense responses to pathogens and to injury and not surprisingly it has similar effects within the central nervous system (CNS). Numerous reports have correlated the presence of IL‐1 in the injured or diseased brain, and its effects on neurons and nonneuronal cells in the CNS, but it is only recently that the importance of IL‐1 signaling has been recognized. This article reviews studies that demonstrate that IL‐1 is at or near the top of the hierarchical cytokine signaling cascade in the CNS that results in the activation of endogenous microglia and vascular endothelial cells to recruit peripheral leukocytes (i.e., neuroinflammation). The IL‐1 system thus provides an attractive target for therapeutic intervention to ameliorate the destructive consequences of neuroinflammation. © 2004 Wiley‐Liss, Inc.