Rett syndrome (RTT) is an X-linked progressive neurodevelopmental disorder that primarily affects females. Mutations in the MECP2 gene have been attributed as the major genetic cause of Rett syndrome. Recently, mutations in CDKL5 and FOXG1 genes have also been suggested to give rise to Rett syndrome, although subsequent more extensive studies suggest that diseases resulting from mutations in these two genes should be considered as distinct clinical entities. While the genetic basis for the Rett syndrome has been recognized, so far there is no effective cure for the disease and the treatments available are mainly aimed at ameliorating clinical problems associated with the disorder. The swift identification of the mutations in children is crucial for pursuing the best therapeutic care. RettBASE was created in 2002 as a MECP2 variant database and has grown to become a comprehensive variant database for Rett syndrome and related clinical phenotypes, containing a curated collection of variants for MECP2, CDKL5 and FOXG1 genes. Here we describe the development and growth of RettBASE after its inception in 2001. Currently, RettBASE holds a total of 4668 variants in MECP2, 498 variants in CDKL5 and 64 variants in FOXG1. This article is protected by copyright. All rights reserved.