Through a regulated or fortuitous phenomenon, small portions of cell nucleic acids are thrown into circulation. Since the discovery of these circulating nucleic acids (CNAs) in 1948, numerous studies have been published to elucidate their clinical implications in multifarious diseases. Scientists have now discovered disease-specific genetic aberrations, such as mutations, microsatellite alterations, epigenetic modulations (including aberrant methylation), as well as viral DNA/RNA from nucleic acids in plasma and serum. CNAs have become increasingly popular due to their potential for use as a liquid biopsy, which is a tool for non-invasive diagnosis and monitoring of diseases, such as cancer, stroke, trauma, myocardial infarction, autoimmune disorders, and pregnancy-associated complications. While the diagnostic potential of CNAs has been investigated extensively, there is a paucity of understanding of their pathophysiological functions. Are these CNAs part of the cell's regular framework of functioning? Or do they act as molecular players in disease initiation and progression? The aim of this review is to investigate the origins and functions of the circulating cell-free nucleic acids in the plasma and serum of patients with various malignancies, and propose areas of study, which may elucidate the novel underlying mechanisms that are functioning during cancer initiation/progression.