Astrocytes in vitro readily respond to a wide variety of neuronal and systemic signals by inducing a complex pattern of early response genes (ERGs). The level of complexity is evident in both the ligand-associated expression kinetics and levels of message accumulation as well as in the heterogeneity of response within a population of astrocytes. Ligand-restricted expression of ERG mRNAs suggest that all astrocytes in culture are not alike. Although the ability of glial cells to express ERGs appears to be highly restricted in vivo, one important exception is the category of glial response to injury. Long-term expression of multiple ERG proteins in glial cells stimulated by neuropathological conditions may play an important role in the outcome of brain injury and neurodegenerative disease. The extensive and staggered expression of ERG proteins acting as transcription factors may represent a mechanism for temporally coordinating the genomic program of large sets of genes associated with glial cell response to neuronal dysfunction. As part of the neuronal-glial interdependency, glial ERG expression may encode and integrate the environmental signals associated with neuronal damage and promote the proper restoration of neuronal function. For example, ligand-induced ERG expression regulates the transcription of the nerve growth factor (NGF) gene in glia which could have important functional consequences on neuronal survival and process outgrowth. Future studies will clarify the mechanisms that lead to the expression of ERGs and the subsequent complex, temporally ordered combinatorial consequence of numerous ERG proteins acting as transcription factors impinging upon target gene promoters. Such studies will enrich our understanding of astrocyte-neuronal interaction, clarify how distinct sets of genes in glial cells contribute to the problem and/or solution of neuropathological situations and guide our efforts to diagnose and treat neuropathological conditions.