The methylation state of lysine residues in histone proteins is a major determinant for formation of active and inactive regions of the genome and is crucial for 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 can catalyze the demethylation of mono-, di-, and tri-methyl lysine residues via an oxidative reaction that requires iron and ?-ketoglutarate. Based on homology, both humans and mice contain at least 30 such proteins, which can be divided into 7 separate families. The JARID (Jumonji/AT-rich interactive domain-containing protein) family contains four members: JARID1A (also RBP2 and RBBP2), JARID1B (also PLU-1), JARID1C (also SMCX), and JARID1D (also SMCY). In addition to the JmJC domain, these proteins contain JmJN, BRIGHT, C5HC2 zinc-finger, and PHD domains, the latter of which binds to methylated histone H3 (Lys9). All four JARID proteins demethylate di- and tri-methyl histone H3 Lys4; JARID1B also demethylates mono-methyl histone H3 Lys4. JARID1A is a critical RB-interacting protein and is required for Polycomb-Repressive Complex 2 (PRC2)-mediated transcriptional repression during ES cell differentiation. A JARID1A-NUP98 gene fusion is associated with myeloid leukemia. JARID1B, which interacts with many proteins including c-Myc and HDAC4, may play a role in cell fate decisions by blocking terminal differentiation. JARID1B is overexpressed in many breast cancers and may act by repressing multiple tumor suppressor genes, including BRCA1 and HOXA5 . JARID1C has been found in a complex with HDAC1, HDAC2, G9a, and REST, which binds to and represses REST target genes in non-neuronal cells. JARID1C mutations are associated with X-linked mental retardation and epilepsy. JARID1D is uniquely localized to the Y chromosome, and functions as a tumor suppressor by repressing genes associated with cell invasiveness. JARID1D is frequently mutated in metastatic prostate tumors, and low JARID1D levels are associated with poor prognosis in prostate cancer patients.