The zebrafish has become a useful model organism for research on development and diseases. However, there has been no zebrafish model system for studying oral carcinogenesis. In the present study, we first characterized the histology of the upper gastrointestinal tract of zebrafish. We found that zebrafish tongue was covered by a non-keratinized stratified squamous epithelium, which was similar to the oro-esophageal epithelium in humans. In situ hybridization showed that keratin 5, a marker of the basal cell layer of mammalian oral epithelium, was expressed in the squamous epithelium of zebrafish tongue. A highly conserved promoter of zebrafish keratin 5 was cloned to drive transgenic expression of GFP. GFP was found to be expressed in the periderm of embryos. In adult fish, GFP was also abundantly expressed in the tongue and fin. GFP expression in transgenic fish recapitulated endogenous zebrafish keratin 5 gene expression as shown by in situ hybridization. This study indicated a high fidelity of GFP reporter gene expression in the tongue under the control of zebrafish keratin 5 promoter. This zebrafish transgenic model system may be used for future studies on oral development and cancer.