Background: Cell-free DNA (cfDNA) is a fragmented DNA that is released into the blood through necrosis, apoptosis, phagocytosis, or active secretion. cfDNA includes a subclass called circulating tumor DNA (ctDNA) released from cancer cells and constitutes a varied proportion of the total cfDNA. Both cfDNA and ctDNA hold significant potential as diagnostic biomarkers in gastrointestinal cancers. Summary: cfDNA and ctDNA are promising diagnostic biomarkers for gastrointestinal cancers with varied diagnostic values in different types of cancers. cfDNA offers higher sensitivity that makes it more suitable for screening methods and constant monitoring, particularly in integration with conventional biomarkers or in a multimarker model. On the contrary, ctDNA gives a real-time picture of tumor genetics and is more suitable for definitive diagnosis due to its specificity for tumor-associated alterations. Different types of samples and methods of detection can influence sensitivity, and the amount of cfDNA is higher in serum but plasma is used for cfDNA analysis because it contains less cellular contamination. In summary, cfDNA is more sensitive than ctDNA, although they have comparable or slightly lower specificity. Key Message: Further studies are needed to create common guidelines, minimize the cost of analysis, and perform extensive clinical trials to demonstrate the utility of circulating cfDNA and ctDNA in the vast majority of gastrointestinal cancer stages. Therefore, with the advancement in these technologies, cfDNA and ctDNA will be highly beneficial and evolve cancer diagnostics and therapy. © 2024 S. Karger AG, Basel.