Cell-free DNA (cfDNA) is a fragmented genomic DNA that is found free in body fluids primarily. In cancer patients, a certain proportion of cfDNA originates from tumor cells when it is called circulating-tumor DNA (ctDNA), and carries information about genetic and epigenetic changes of neoplastically transformed cells. This is the basic postulate that defines cfDNA, or ctDNA, as a potential tumor biomarker. Routine applications of tissue biopsy are invasive, sometimes difficult or impossible, which encourages the development of new non-invasive approaches and related technologies. Therefore, in recent years, the potential use of nsDNA as a non-invasive tumor biomarker that is readily available especially in a patient's peripheral blood is receiving much attention. Cell-free DNA from liquid biopsies is an ideal noninvasive tumor biomarker with the ability of frequently repeated sampling and analysis with virtually no stress for an oncology patient. In clinical oncology, cfDNA analysis from liquid biopsy has potential application in screening, early tumor diagnosis, evaluation of therapies, monitoring disease progression, identifying the development of resistance to therapy, and predicting disease outcomes in general. Despite the rapid and strong development of this approach and related technologies, many challenges still need to be successfully addressed.