Astrocyte activation and reactive gliosis are seen in many neuropathologies, e.g., neurotrauma, stroke, epilepsy, or neurodegenerative diseases. Astrocyte activation alters gene expression and leads to morphological and functional changes in astrocytes with important functional consequences for the central nervous system (Eddleston and Mucke, Neuroscience 54:15-36, 1993; Eng and Ghirnikar, Brain Pathol 4:229-237, 1994; Hernandez et al., Glia 38:45-64, 2002; Pekny and Nilsson, Glia 50:427-434, 2005; Wilhelmsson et al., Proc Natl Acad Sci U S A 103:17513-17518, 2006; Sofroniew, Trends Neurosci 32:638-647, 2009; Sofroniew and Vinters, Acta Neuropathol 119:7-35, 2010). The understanding of astrocyte activation and reactive gliosis in pathological situations remains incomplete but the increasing amount of experimental evidence points to its importance in disease pathogenesis (Wilhelmsson et al., J Neurosci 24:5016-5021, 2004; Sofroniew, Neuroscientist 11:400-407, 2005; Maragakis and Rothstein, Nat Clin Pract Neurol 2:679-689, 2006; Seifert et al., Nat Rev Neurosci 7:194-206, 2006; Correa-Cerro and Mandell, J Neuropathol Exp Neurol 66:169-76, 2007; Barres, Neuron 60:430-440, 2008; Li et al., J Cereb Blood Flow Metab 28:468-481, 2008; Macauley et al. J Neurosci 31:15575-15585, 2011). One of the principal hallmarks of astrocyte activation and reactive gliosis is the upregulation of astrocyte intermediate filament (nanofilament) proteins and reorganization of intermediate filaments that are part of the cytoskeleton. This review focuses on the role of the intermediate filament system of astrocytes in neuropathological context and presents some of the relevant model systems.