Background: Gastrointestinal cancers (GICs) are classified based on both organ and tissue of origin, but might be better classified based on their molecular profile. We performed a multiplatform biomarker analysis of the main 17 types of GICs to identify molecular abnormalities and their associations. Methods: We analyzed 11,324 cases of GIC (96% from USA) using gene sequencing (up to 44 different genes, Sanger, NGS), protein expression by immunohistochemistry (up to 28 gene products) and gene amplification by CISH or FISH (up to 8 genes). Further, we performed heat map analysis of the 70 molecular anomalies in 17 GIC sites. Results: Steroid receptor (ER, PR) expression was distinctively high in neuroendocrine cancers (CA) (10-40%) while AR expression was elevated in hepatocellular carcinoma (HCC) (20%). HER2 overexpression and amplification was distinctively elevated in gastric, GEJ, esophageal and gall bladder CA (up to 20%). Overexpression of TOP2a was noted in most of the GICs, reflecting their highly proliferative and aggressive nature. Overexpression of cMET (up to 82%) and EGFR amplification (up to 32%) was noted in a majority of GICs suggesting benefit from cMET and EGFR targeted therapies. HCC had a high frequency of CTNNB1 (19%, 11/58) and low frequency of ABL1 mutation (3%, 2/59). Distribution of APC mutations in GIC ranged from 10-73%. PIK3CA mutation and PTEN loss were frequent events (up to 15% and 89% respectively) in a majority of GIC, suggesting potential benefit of targeting the PI3K pathway. Based on the RAS/RAF and PI3K/PTEN/Akt/mTOR pathway alterations, colon and rectal CA share similar molecular signatures but gall bladder and biliary tract CA, as well as colon and appendix CA, are molecularly distinct. Small bowel and duodenal CA exhibited different molecular signatures based on APC, ATM, SMAD4 and p53 mutations. Conclusions: Molecular profiling of GICs might allow us to reconsider clinical trial design and disease management based on individual cancer molecular abnormalities. Protein expression and copy number alterations should be considered together with mutational analysis to refine cancer treatment in GI tract malignancies.