Cell-free DNA (cf-DNA), which is released into circulation following cellular death and tissue injury, has recently emerged as a promising new indicator of the degree of the damage. In addition to assessing the quantities of circulating cf-DNA, qualitative features, such as the cf-DNA methylation level and fragment size distribution have been demonstrated to be useful diagnostic and prognostic markers in various pathologies. The fact that virtually every cell in the body can release cf- DNA makes this measure a highly sensitive indicator of homeostatic disturbances and alterations in the rate of cellular death. However, despite the growing utility of cf-DNA assessment, many aspects regarding the regulation of circulating cf-DNA levels and alterations in the composition of the total cf-DNA pool in physiological conditions, such as aging, are currently unknown. Likewise, it is unclear whether cf- DNA is merely a risk-indicating biomarker or whether it can acquire a pathogenic role in certain conditions.