Grainyhead-like-2 (GRHL2), a mammalian homolog of Drosophila grainyhead (GRH), is involved in a variety of biological processes, including mammalian embryonic development, epidermal barrier maturation, epithelial wound healing, and central nervous system development. Notably, GRHL2 is also essential for tumor origination and development in various kinds of cancer tissues, such as hepatocellular carcinoma, breast cancer and oral squamous cell carcinoma. In these cancer cells, GRHL2 expression is markedly enhanced, and the gain of GRHL2 can significantly facilitate cancer cell proliferation and inhibit apoptosis. On contrast, in epithelial-mesenchymal transition (EMT) related breast cancer, the down-regulated GRHL2 can promote the EMT process. The underlying mechanisms of GRHL2 in tumorigenesis remain complex and diverse, including the death receptor-mediated apoptosis, aberrant activation of the human telomerase reverse transcriptase(hTERT), EMT, and enhanced anoikis-sensitivity as well. We believe that further research on GRHL2 may cast new lights on cancer therapy.