INTRODUCTION: The pressing need to determine the KRAS/BRAF mutational status for selecting patients with colorectal cancer (CRC) for anti-EGFR therapy provides a great opportunity to use circulating DNA (ctDNA) as a theranostic tool for personalized medicine. Better understanding of ctDNA origin (necrosis, apoptosis and active release) may increase the reliability of using abnormal ctDNA as biomarker. AREAS COVERED: The authors showed that examining the proportion of ctDNA originating from tumor, microenvironment and normal cells, through size distribution and mutation load may help to discriminate mechanisms of ctDNA release. EXPERT OPINION: Contrary to the literature, it was observed that tumor-derived ctDNA was mostly shorter than 100 bp. Tumor-derived ctDNA from cancer patients exhibited a specific ctDNA size distribution profile and significantly higher ctDNA fragmentation than ctDNA from healthy individuals. Examination of the KRAS and BRAF mutational load in 48 mutated samples revealed very high variation ranging from 0.037 to 68.8%. This suggests either that tumor cells variably release ctDNA compared with tumor-associated stroma cells or normal cells, or that mutant ctDNA analysis may depend on tumor clonality. Detection of point mutation by quantifying the proportion of mutant ctDNA fragments provides a powerful tool for assessing the proportion of ctDNA from different origins.