The identification of transcription factors TTF 1 and Pax 8 and the demonstration of their pivotal role in thyroid development and in the control of thyroid-specific gene expression, although representing remarkable openings in our understanding of cell-specific transcription in the thyroid, still leave a lot of open questions. Recent work investigating the development of thyroid-specific gene expression in transgenic mouse models, now reveal that some basic assumptions have to be reconsidered also. Altogether, currently available data indicate that the regulatory machinery undergoes significant changes during thyroid organogenesis and confirm the existence of still unknown factors whose roles appear at least as critical as the ones played by TTF 1 and Pax 8 in the control of specific gene expression.