Cancer is the second most common culprit of mortality in the United States and epithelial carcinomas are considered as one of the most predominant types of cancer. The association between epithelial cancers and paired-box gene 8 (PAX8) has been studied significantly before. PAX8 belongs to the paired-box gene family, which plays an important role in the organogenesis of different body organ systems, especially the thyroid gland, the renal system, and the Müllerian system. Immunohistochemical staining is being used to detect PAX8 expression in different epithelial cancers and differentiate them from PAX8-negative tumors. In follicular, papillary, and anaplastic thyroid carcinomas, targeting the PAX8/peroxisome proliferator-activated receptors (PPARs) fusion protein is being considered as a potential mechanism for therapy. Moreover, because of its high expression in primary ovarian cancers, PAX8 is being considered as a target for ovarian cancer treatment as well. More studies are needed to test the possibility of using PAX8 as a possible target for managing endometrial carcinomas. In this article, we review the functions of the PAX8 gene, how its mutations lead to the development of certain epithelial carcinomas, how it can be used as a diagnostic or a prognostic marker, and its potential as a therapeutic target for these cancers.