Rett syndrome (MIM 312750) is a neurodevelopmental disorder of unknown cause that primarily affects girls (Naidu Naidu, 1997). The clinical picture is enigmatic for the normal perinatal period, followed by rapid deceleration of head growth during early childhood, with loss of purposeful hand movements and apraxia. Approximately 99.5% of cases are isolated, with no other affected relative. The mode of inheritance has been hotly debated, with models of both X-linked and sex-influenced autosomal inheritance advanced to explain the preponderance of isolated female cases. We describe a family with the largest number of female siblings affected with Rett syndrome identified to date, and we have used data from this family, as well as from families previously described (Ellison et al. Ellison et al., 1992; Schanen et al. Schanen et al., 1997; Xiang et al. Xiang et al., 1998), to demonstrate X-linked dominant inheritance and to localize the responsible locus to Xq28.