Abstract Liquid biopsies are a valuable non-invasive biomarker source for the diagnosis, prognosis and monitoring of cancer patients. The detection of circulating cell-free DNA (cfDNA) derived from tumor cells (ctDNA) has emerged as a promising clinical approach, as their levels are elevated in many cancers and contains tumor-related mutations and specific methylation patterns. ctDNA can be released from tumor cells into the bloodstream, either linked to extracellular vesicles (EV-DNA) or in an EV-free form when associated with nucleosomes and other proteins, or even as a component of macromolecular structures such as neutrophil extracellular traps (NET DNA). These different types of cfDNA can mirror cancer progression and predict patient outcome. This review presents the recent benefits of cfDNA in cancer, distinguishing between EV-DNA and EV-free DNA, and highlights their clinical utility.