Discs large homolog 5 (DLG5), a key member of the membrane-associated guanylate kinase (MAGUKs) family, is a scaffold molecule for signal transduction complexes and is responsible for assembling receptors and adapters. This scaffold protein stabilizes adhesion and tight bonding complexes in many organs and tissues, and is involved of maintaining epithelial polarity. Although DLG5 plays a role in normal development in mice, it has also been linked to the onset and development of several diseases, particularly Crohn's disease and various malignancies. DLG5 has been shown to impact the progression of cancer through direct or indirect interactions with H-catenin, E-cadherin, Vimentin, p53, P21, Cyclin D1, TGF-β1, AKT, Hippo, and classic G protein signaling pathways. DLG5 and DLG5 variants has been found to have a dual role in human diseases. Although it is overexpressed in pancreatic adenocarcinoma, its expression is reduced in lung, liver, breast, prostate, and bladder cancers. However, two independent studies on glioblastoma (GBM) have shown the opposite effects of DLG5. Our study evaluates the existing literature on the role of DLG5 and DLG5 variants in disease processes, and summarizes the available data on the role of DLG5 in disease based on cell experiments, clinical samples, and animal models, while highlighting its future potential in disease treatment.