The development of endoscopic surgery and improvements in video technology during the past 15 years offered new horizons for many surgical disciplines. These techniques were adopted also for endoscopic procedures on the thyroid gland. Different endoscopic approaches for thyroidectomy have been described in the past years: they could be divided into cervical, minimal incision, approaches and extracervical approaches. The later ones are most widespread in the Asian region since the demand on perfect cosmetic outcomes and no visible scars in the neck region are higher here. The extracervical approaches do not appear to be minimally invasive: due to the large amount of subcutaneous dissection to reach the target area they could be addressed as being maximally invasive. We have developed a new trans-oral endoscopic and minimally invasive approach through the floor of mouth to combine minimally invasive access and perfect cosmetic outcome. Moreover this approach is gentler since anatomically defined layers of the neck are entered directly and postoperative sequelae like swallowing disorders are minimized. In preclinical anatomical and animal studies the approach could be developed and first clinical applications proved its feasibility and safety. The trans-oral endoscopic thyroidectomy and all preclinical and clinical studies are outlined in this chapter.