Grainyhead-like 2 (GRHL2), an mammalian homolog of Drosophila grainyhead, is associated with age-related hearing impairment repair, neural tube closure, epidermal integrity, and wound healing; it also takes part in the initiation and progression of cancer. As the research going on, GRHL2 has been proven to be of great importance in different molecular mechanisms of different types of cancer. We herein reviewed the biological functions of GRHL2 family and the roles of GRHL2 proteins in digestive system neoplasms, hoping to lay a foundation for more advanced research of GRHL2.