The transcription factor Ikaros (Ik) is at the centre of a functionally diverse chromatin-remodeling network that is critical for the development and regulation of both the immune and endocrine systems. Dominant negative forms of Ik result in neoplastic growth in mouse genetic studies and have been identified in human tumors. Ik modulates chromatin accessibility through associations with members of the NURD complex including histone deacetylase complexes (HDAC). We show here that Ik expression in mouse pituitary corticotroph cells is itself regulated through histone modifications as well as DNA methylation. Examination of primary human pituitary specimens also identified a correlation of loss of Ik expression with the presence of DNA methylation in untranslated exon 1 CpG island. These findings have important implications for the understanding of Ikaros' role in epigenetic functions and suggest a potential role for demethylating agents in the treatment of related disorders.