Variations in the transcription factor Gli-similar 3 (GLIS3) gene have been associated to variable congenital endocrine defects, including both morphogenetic and functional thyroid alterations. Evidence from Glis3 knockout mice indicates a relevant role for GLIS3 in thyroid hormone biosynthesis and postnatal thyroid gland growth, with a mechanism of action downstream of the TSH/TSHR interaction. However, the pathophysiological role of this transcription factor during the embryonic thyroid development remains unexplored. In this manuscript, we will provide an overview of the current knowledge on GLIS3 function during development. As a perspective, we will present preliminary evidence in the zebrafish model in support of a potential role for this pleiotropic transcription factor in the early stages of thyroid gland development.