Translational research of liquid biopsy is just at the edge of routine clinical application: an emerging validity of circulating tumor DNA (ctDNA) tests suggests its use for earlier cancer detection and better monitoring of minimal residual disease (MRD) and resistance development, thus offering earlier guidance for therapy choices with the intent to cure cancer. In this review, we focus on ctDNA as an advanced and standardized validated marker in liquid biopsy. We also discuss what will be needed to reach the new milestone of personalized (precision) medicine to be used as a common standard of care. We summarize recent developments of cell-free DNA (cfDNA) and its clinical use as a biomarker in cancer.