Advances in molecular research in cancer have brought new therapeutic strategies into clinical usage. One new group of targets is tyrosine kinase receptors, which can be treated by several strategies, including small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Aberrant activation of growth factors/receptors and their signal pathways are required for malignant transformation and progression in gastrointestinal (GI) carcinomas. The concept of targeting specific carcinogenic receptors has been validated by successful clinical application of many new drugs. Type I insulin-like growth factor (IGF) receptor (IGF-IR) signaling potently stimulates tumor progression and cellular differentiation, and is a promising new molecular target in human malignancies. In this review, we focus on this promising therapeutic target, IGF-IR. The IGF/IGF-IR axis is an important modifier of tumor cell proliferation, survival, growth, and treatment sensitivity in many malignant diseases, including human GI cancers. Preclinical studies demonstrated that downregulation of IGF-IR signals reversed the neoplastic phenotype and sensitized cells to anticancer treatments. These results were mainly obtained through our strategy of adenoviruses expressing dominant negative IGF-IR (IGF-IR/dn) against gastrointestinal cancers, including esophagus, stomach, colon, and pancreas. We also summarize a variety of strategies to interrupt the IGFs/IGF-IR axis and their preclinical experiences. Several mAbs and TKIs targeting IGF-IR have entered clinical trials, and early results have suggested that these agents have generally acceptable safety profiles as single agents. We summarize the advantages and disadvantages of each strategy and discuss the merits/demerits of dual targeting of IGF-IR and other growth factor receptors, including Her2 and the insulin receptor, as well as other alternatives and possible drug combinations. Thus, IGF-IR might be a candidate for a molecular therapeutic target in human GI carcinomas.