Reactive astrogliosis is the most prominent macroglial response to diverse forms of CNS injury. We assessed a potential role for the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway because it represents a common effector for several major families of transmembrane receptors implicated in astrogliosis. Immunohistochemical detection of activated ERK/MAPK in a series of human neurosurgical specimens utilizing phosphorylation state-dependent antibodies consistently revealed intense immunoreactivity in reactive astrocytes in both subacute and chronic lesions, including infarct, mechanical trauma, chronic epilepsy, and progressive multifocal leukoencephalopathy. Neurons, oligodendroglia, and most inflammatory cells showed little or no detectable activation. These observations suggest a testable hypothesis: activation of the ERK/MAPK pathway is an obligatory step for the triggering and/or persistence of reactive astrogliosis.