The methylation state of lysine residues in histone proteins is a major determinant of the formation of active and inactive regions of the genome and is crucial for the proper programming of the genome during development. Jumonji C (JmjC) domain-containing proteins represent the largest class of potential histone demethylase proteins. The JmjC domain of several proteins has been shown to catalyze the demethylation of mono-, di-, and trimethyl lysine residues via an oxidative reaction that requires iron and alpha-ketoglutarate. Based on homology, both humans and mice contain at least 30 such proteins, which can be divided into seven separate families. The JMJD1 (Jumonji domain-containing protein 1) family, also known as JHDM2 (JmjC domain-containing histone demethylation protein 2) family, contains four members: hairless (HR), JMJD1A/JHDM2A, JMJD1B/JHDM2B, and JMJD1C/JH- DM2C. Hairless is expressed in the skin and brain and acts as a co-repressor of the thyroid hormone receptor. Mutations in the hairless gene cause alopecia in both mice and humans. JMJD1A is expressed in meiotic and post-meiotic male germ cells, contributes to androgen receptor-mediated gene regulation, and is required for spermatogenesis. It has also been identified as a downstream target of OCT4 and STAT3 and is critical for the regulation of self-renewal in embryonic stem cells. JMJD1B is a more widely expressed family member and is frequently deleted in myeloid leukemia. JMJD1C (also known as TRIP8) is a co-factor of both the androgen and thyroid receptors and has a potential link to autism. Members of the JMJD1/JHDM2 family have been shown to demethylate mono-methyl and di-methyl histone H3 (Lys9).