In the past 20 years there have been great advances in our understanding of the molecular genetics of gastrointestinal tumors. In general, cancers develop and proliferate due to: driver mutations or related alterations in the genome resulting in overactivity of oncogenes, underactivity of tumor suppressor genes allowing tumors to grow, and impaired DNA repair mechanisms either from sequential mutations with or without germline mutations predisposing patients to cancer. Infections such as hepatitis B and C, and Human Papilloma Virus (HPV) can lead to hepatocellular cancers and anal cancers, respectively. This genomic knowledge has helped us better define unique subsets within diseases like colon and pancreatic cancer which may benefit from precisely targeted therapies. Alterations in key proteins on tumors and in the tumor microenvironment can be targets for molecular-targeted radiopharmaceutical therapies, immunotherapies and other targeted treatments. Molecular imaging may be deployed more aggressively in high-risk groups for possible detection of tumor occurrence, progression, and response to therapy. This chapter provides a brief summary of the genomics of gastrointestinal tumors, selected examples of targeted therapies, and examples of how current and emerging molecular imaging tools, assessing the tumor phenotype, inform our management of patients with tumors.