This review presents historical and clinical information on the rare human brain disorder known as Alexander disease (ALX), and reports on the recent discovery of the gene that appears to be causative. The disease is a fatal, white matter disorder (leukodystrophy) of childhood. Adult onset cases also have been described, but it has not been clear whether they represent the same disease. Until recently the diagnosis was made by the pathological examination of brain tissue, in which abundant Rosenthal fibers were found. These abnormal structures occurred within astrocytes, but their composition was unclear. In 1985, a child underwent a diagnostic brain biopsy at this institution, which established the diagnosis of ALX. Ultrastructural immunocytochemistry revealed that the Rosenthal fibers contained abundant amounts of glial fibrillary acidic protein (GFAP), a normal component of astocytic intermediate filaments. Thus, the gene for this filament protein was considered a candidate gene for the cause of ALX, and DNA samples from children presumed or proven to have this disorder were banked for future study. Other work on the same brain biopsy showed that Rosenthal fibers also contained abundant alphaB-crystallin, a heat shock protein, but no defect was found in its gene. A decade after the biopsy, a transgenic mouse with an extra copy of the gene for GFAP was produced. These mice died early and their brains contained Rosenthal fibers. Although not an exact model for ALX, this also suggested that the gene for GFAP should be considered a candidate gene for ALX. Subsequent research has demonstrated that the great majority of childhood ALX cases contain mutations in the gene for GFAP. This work is now being extended as a diagnostic test, as well as to seek understanding of the pathogenesis of ALX and possible approaches for treatment.