In a cohort of 103 females clinically diagnosed with Rett syndrome (RTT), 91 had a detectable MECP2 mutation. Emphasis on details of natural history facilitated grouping of females with the same MECP2 mutation and the development of so-called disorder profiles. Some examples of disorder profiles of different recurrent MECP2 mutations are discussed. RTT females with the frequently recurrent R133C and R306C missense mutations and those with intragenic deletions in the C-terminus of MECP2 deserve more attention in larger studies as their development is different and milder in the long term. RTT females with the T158M missense mutation are often atypical with mainly behavioral characteristics in infancy and childhood but become classic RTT in adolescence after a slower, protracted course. © 2009 Wiley-Liss, Inc.