The role of DNA methylation in immune function is discussed extensively in other papers in this issue. Many of these discussions assume that DNA methylation, a major mediator of epigenetic information, is fairly immutable and uniform in adult cells and tissues. There is, however, growing evidence that DNA methylation changes subtly with age. Normal aging cells and tissues show a progressive loss of 5-methylcytosine content, primarily within DNA repeated sequences, but also in potential gene regulatory areas. In parallel, selected genes show progressive age-related increases in promoter methylation, which, once a critical methylation density is reached, have the potential to permanently silence gene expression. These changes are highly mosaic within a given tissue and introduce a high degree of epigenetic variability in aging cells. Such epigenetic phenomena could impact immune response through masking/unmasking potential tissue antigens as well as by modulating the differentiation and response of immune effector cells. The contribution of epigenetic changes to the altered immune function observed in aging humans deserves careful investigation.