Background: Liquid biopsy of circulating tumor DNA (ctDNA) is a novel method of detecting genetic alterations in cancer patients without tissue acquisition. Methods: Our analysis surveyed the genomic landscape of 213 patients with various gastrointestinal malignancies using next generation sequencing of plasma ctDNA across a 68 gene panel (www.guardanthealth.com/guardant360/). Data analysis was performed following UCSD IRB guidelines for de-identified database (NCT02478931). Results: The most common cancer types were colorectal adenocarcinoma (N = 55 (26%)), appendiceal adenocarcinoma (N = 46 (22%)), hepatocellular carcinoma (N = 31 (15%)), and pancreatic ductal adenocarcinoma (N = 25 (12%)). 70% of patients had discernible alteration(s), and 58% of patients had ≥1 characterized alterations. The median number of characterized alterations per patient was 1 (range 0-13). The number of detected alterations per patient varied between cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had > 1 characterized alteration(s), whereas 76% of patients (35/46) with appendiceal adenocarcinoma had no characterized alterations. Overall, of 123 patients with characterized alterations, > 99% (122/123) had ≥1 hypothetical (experimental or approved) treatment options available. Potentially targetable alterations varied between cancer types, proportionally to the detection rate of characterized alterations. The median percent ctDNA of characterized alterations was 2.50% (IQR 0.76-8.96%). Of interest, 95% of patients (117/123) had distinct molecular portfolios. Altogether, there were 143 unique characterized alterations within 56 genes. Overall concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy (105 patients) (https://www.foundationmedicine.com/) in the four most common alterations (KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Conclusions: Our observations suggest that many patients with gastrointestinal tumors have discernible and pharmacologically tractable ctDNA alterations. Hence, ctDNA assessment through non-invasive liquid biopsy may have an important role in clinical practice.