The first treatment for hypothyroidism introduced at the end of the 19th century was animal thyroid extract which contained both T3and T4. Because of variable potency it was widely replaced by synthetic T4 from the 1960s in high doses of 200-400 ug daily to compensate for the lack of T3. The development of TSH assays showed that a dose of T4 of 100-150 ug daily was usually adequate to restore serum TSH to normal. Because a suppressed serum TSH has been shown to be a risk factor for osteoporosis, atrial fibrillation, and most recently for excess cardiovascular mortality, there is a consensus that the correct treatment of hypothyroidism is a dose of thyroxine which restores euthyroidism and maintains both T4 and TSH in their respective reference ranges. However, a significant minority of patients only achieve the desired sense of well-being if serum TSH is suppressed. Furthermore, patients rendered hypothyroid following treatment of thyrotoxicosis and taking a dose of T4 which maintains a normal TSH, gain more weight than those who do not become hypothyroid. Studies in hypothyroid rats suggest that it is only possible to restore universal tissue euthyroidism using a combination of T3and T4. In patients in whom long-term T4 therapy was substituted by the equivalent combination of T3 and T4 scored better in a variety of neuropsychological tests. It would appear that the treatment of hypothyroidism is about to come full circle.