These three factors led to a dramatic change in how hypothyroidism was diagnosed and treated, such that in the last 40 years (i) measurement of serum TSH has become the cornerstone of diagnosis and therapeutic monitoring, (ii) the replacement dosage of thyroid hormone has been substantially decreased, and (iii) “monotherapy” with levothyroxine (LT4) has become a universally accepted first-line approach given its excellent safety index. This evidence concerns the gene TG and hypothyroidism.