Sodium levothyroxine is one of the most prescribed drugs all over the world. Oral thyroxine treatment is often used lifelong and the search for optimal daily dose may be a challenge for the physician. Patient age and compliance to prescribed regimen are in fact relevant features to achieve therapeutic goal. Also, the absorption of thyroxine is not a linear function of the ingested dose being sensitive to several interferences. Inaccurate administration modality, thyroxine interaction with different drugs, pregnancy, and malabsorption are all possible causes of increased need for thyroxine. Important and simple evidences are now available to improve the accuracy of drug administration and optimize the treatment. In fact, recent evidence pointed out the role of gastric acid secretion on the subsequent intestinal absorption of thyroxine in relation with the timing of food ingestion as well as with pH impairment associated to frequent gastric disorders like Helicobacter pylori infection and gastric atrophy.