The presence of small amounts of tumor DNA in cell free DNA (CFDNA) circulating in the plasma or serum of cancer patients was first demonstrated 30 years ago. Since then, overall plasma DNA concentration in cancer patients and genetic or epigenetic alterations specific to tumor DNA have been investigated in patients diagnosed with different types of cancer. The proportion of patients with altered CFDNA varies with the pathology and the nature of the marker. However, several studies have reported the presence of altered CFDNA in over 50% of cancer patients, suggesting that this marker may be common and amenable for a variety of clinical and epidemiological studies. Because the mechanisms and timing of CFDNA release in the blood stream are poorly understood, only few studies have addressed the use of CFDNA for early cancer detection or as a biomarker for mutagenesis and tumourigenesis in molecular epidemiology. In this review, we discuss the technical issues involved in obtaining, using and analyzing CFDNA in cancer or healthy subjects. We also summarize the literature available on the mechanisms of CDNA release as well as on cross-sectional or prospective studies aimed at assessing the clinical and biological significance of CFDNA. These studies show that, in some circumstances, CFDNA alterations are detectable ahead of cancer diagnosis, raising the possibility of exploiting them as biomarkers for monitoring cancer occurrence. Testing these hypotheses will require well-designed studies, assessing multiple markers with quantitative and sensitive methods, with adequate follow-up of subjects, and we provide recommendations for the development of such studies.