Detecting alterations in blood cell-free DNA (cfDNA) is hoped to be a novel, noninvasive method for diagnosing, prognosing and monitoring cancer patients. Several studies have assessed the usefulness of measuring tumor-specific genetic and epigenetic changes of cfDNA, such as loss of heterozygosity, frequency of mutations, alterations of microsatellites and the methylation of genes in patient blood samples. However, few well-designed trials have been carried out to translate these findings effectively. In this review, we have assessed the clinical utility of cfDNA in pancreatic, liver and upper gastrointestinal malignancies.