Chromobox 4 (CBX4) is a polycomb group protein involved in epigenetic regulation via the polycomb repressive complex 1 (PRC1) and its small ubiquitin-like modifier (SUMO) ligase activity. It has been reported that CBX4 plays several oncogenic functions, contributing to tumor growth, metastasis, and therapeutic resistance. Elevated CBX4 expression is also correlated with poor patient prognosis and advanced tumor stages in multiple gastrointestinal cancers. Preclinical studies demonstrate that targeting CBX4 using small-molecule inhibitors, RNA interference, and monoclonal antibodies mitigates tumor progression and enhances treatment efficacy. Additionally, CBX4 exhibits potential as a diagnostic biomarker, with its high expression levels serving as an indicator of early-stage disease. Despite these advances, further research is needed to elucidate molecular mechanisms behind CBX4's involvement in carcinogenesis to accelerate the translation of tools and approaches targeting CBX4 to clinical settings. The aim of this paper is to review the role of CBX4 in gastrointestinal cancers, including gastric, liver, colorectal, and esophageal cancers, offering invaluable insights for developing novel diagnostic tools and targeted therapies to improve patient outcomes.