In this work, we tried to clarify the impact of NIS expression (mRNA and protein) on thyroid tumors’ aggressiveness and therapy success and, as a result of the above, the putative prognostic significance of SLC5A5 mRNA and NIS protein expression. Moreover, we also addressed the impact of the genetic background of the tumor on SLC5A5 and NIS expression as well as its targeting to the basolateral cell membrane.