The retinal determinant gene network (RDGN), originally discovered as a critical determinator in Drosophila eye specification, has become an important regulatory network in tumorigenesis and progression, as well as organogenesis. This network is not only associated with malignant biological behaviors of tumors, such as proliferation, and invasion, but also regulates the development of multiple mammalian organs. Three members of this conservative network have been extensively investigated, including DACH, SIX, and EYA. Dysregulated RDGN signaling is associated with the initiation and progression of tumors. In recent years, it has been found that the members of this network can be used as prognostic markers for cancer patients. Moreover, they are considered to be potential therapeutic targets for cancer. Here, we summarize the research progress of RDGN members from biological functions to signaling transduction, especially emphasizing their effects on tumors. Additionally, we discuss the roles of RDGN members in the development of organs and tissue as well as their correlations with the pathogenesis of chronic kidney disease and coronary heart disease. By summarizing the roles of RDGN members in human diseases, we hope to promote future investigations into RDGN and provide potential therapeutic strategies for patients.© 2023. The Author(s).