Using an in vitro model for the differentiation of human blood-derived monocytes into dendritic cells (DCs), we have undertaken an investigation of epigenetic changes that take place at CD14 and CD209 (DC-SIGN) genes that encode cell surface antigens that are crucial for the function of monocytes and DCs, respectively. Upon differentiation the cell surface expression of CD14 is lost, whilst CD209 expression is increased. These reciprocal changes are associated with the loss of epigenetic markers of "activation" at the CD14 locus, but the acquisition of the same at the CD209 locus. There is little change in "repressive" histone marks and CpG methylation at the CD14 locus. By contrast there are changes in both the "repressive" histone marks and CpG methylation at the CD209 locus. In particular, two CpG dinucleotides, designated CpG2 and CpG3, show a marked demethylation at the CD209 promoter upon differentiation. These data provide insight into the epigenetic demands that are necessary to effect the reciprocal changes in expression of the CD14 and CD209 genes upon terminal differentiation of monocytes into DCs. For repression of the active CD14 gene the loss of "activation" histone modifications is likely necessary and sufficient for silencing. By contrast the activation of the silent CD209 gene appears to require an acquisition of "active" histone modifications and concomitant loss of both "repressive" histone marks and CpG methylation.