© Springer Science+Business Media, LLC 2009. All rights reserved. This volume documents the multiple roles astrocytes perform in the normal develo pment and function of the central nervous system (CNS). A nagging question has been that if these roles are as critical as assumed, why have genetic diseases of astrocyte dysfunction not been identified to take their place next to those due to defects in neurons and oligodendrocytes? An explanation casually offered is that these functions are so important that their loss would be embryonic lethal, and thus not be detected. But this is not a satisfactory answer, as mutations that result in a partial loss of function would still be expected. Here we describe the first discovered instance of a primary astrogliopathy, in which a defect in astrocytes indeed results in a human disorder - Alexander disease. Fittingly, the gene encoding glial fibrillary acidic protein (GFAP), the intermediate filament protein that has been the standard marker for astrocytes in both basic and clinical studies, has proved to be the affected target in this disorder. This chapter reviews observations of human patients and model systems in which the focus has been on the role of GFAP. A number of excellent reviews discuss findings prior to the advent of this gene test (e.g., see Herndon et al., 1970; Spalke and Mennel, 1982; Becker and Teixeira, 1988; Pridmore et al., 1993; Reichard et al., 1996; Gordon, 2003; Jacob et al., 2003; Messing and Goldman, 2004).