S tromal-derived cell factor-1α (SDF-1α; CXCL12) and its receptor, CXCR4, are constitutively expressed on neuroepithelial cells and are believed to be involved in both development and pathological processes, such as AIDS-associated neurologic disorders. Here, we demonstrate that SDF-1α activates NF-κB, stimulates production of chemokines and cytokines, and induces cell death in primary astrocytes, effects that depend on ongoing secretion of TNF-α. SDF-1α upregulated TNF-α mRNA and protein secretion, as well as TNF receptor 2 expression. TNF-α treatment mimicked SDF-1α induction of NF-κB, IL-1α/β, and RANTES, as well as cell death; neutralizing antibodies against TNF-α opposed these responses. We also found that SDF-1α activated Erk1 and Erk2 (Erk1/2) MAPK in a biphasic fashion. Early Erk1/2 activation was stimulated directly by SDF-1α and late activation was mediated by TNF-α. PD98059 suppression of early Erk1/2 activation correlated with reduction of SDF-1α–induced TNF-α expression. Late Erk1/2 activation was involved in TNF-α–stimulated NF-κB activation and cytokine induction. SDF-1α was induced in reactive CXCR4-positive astrocytes near axotomized spinal cord motor neurons, consistent with autocrine SDF-1/CXCR4 signaling in these cells. We propose that these novel effects of SDF-1α are relevant to the pathogenic and developmental roles of SDF-1α in the CNS.