The human erythropoietin gene is expressed predominantly in the kidney and liver in response to hypoxia. Although the signaling cascade for hypoxia is present in many different cell types, the expression of erythropoietin is restricted to only a few tissues. The authors show that the promoter and 5′-untranslated region (5′-UTR) of the erythropoietin gene comprise a CpG island and that methylation of the CpG island correlates inversely with expression. Methylation represses the expression of the erythropoietin gene in 2 ways: high-density methylation of the 5′-UTR recruits a methyl-CpG binding protein to the promoter, and methylation of CpGs in the proximal promoter blocks the association of nuclear proteins. (Blood. 2000;95:111-119)