Effects of thyroid hormones in individual tissues are determined by many factors beyond their serum levels, including local deiodination and expression and activity of thyroid hormone transporters. These effects are difficult to examine by traditional techniques, but a novel approach that exploits the existence of common genetic variants has yielded new and surprising insights. Convincing evidence indicates a role of type 1 iodothyronine deiodinase (D1) in determining the serum T₄:T₃ ratio and a role of phosphodiesterase 8B in determining TSH levels. In addition, studies of type 2 iodothyronine deiodinase (D2) variants have shown that thyroid hormones contribute to osteoarthritis and these variants influence Intelligence quotient alterations associated with iodine deficiency. Preliminary evidence suggests associations between TSH-receptor variants and fasting glucose level, D1 variants and insulin-like growth factor I production, and D2 variants and hypertension, psychological well-being and response to T₃ or T₄ treatment. Intriguingly, most of these associations are independent of serum thyroid hormone levels, which highlights the importance of local regulation of thyroid hormones in tissues. Future research might reveal novel roles for thyroid hormones in obesity, cardiovascular disease, osteoporosis and depression and could have implications for interpretation of thyroid function tests and individualization of thyroid hormone replacement therapy.