Many processes are involved between ingesting thyroid hormone and the hormone having an effect within cells. These include hormone absorption, transport into cells, deiodination (for activation and inactivation), export from cells, receptor binding, and activation. Rare, major single gene defects have been reported at many though not all of these steps. Genome wide analyses have also identified multiple common loci associated with TSH and to lesser extent FT4 and FT3 levels. Since variation in thyroid hormone levels between individuals even within the reference range has effects on disease processes such as hypertension, cardiovascular disease, metabolic syndrome, and bone density, the effect of these variants on an individuals set point for thyroid function may be relevant to considering thresholds for thyroid hormone replacement. Rare variants with major effect in a small number of individuals may not yet have been identified. The effects of genetic variation in factors beyond the serum level of thyroid hormone are likely to also affect disease processes. Common, functional variants are difficult to define, and attention has focussed on the Thr92Ala variant in deiodinase 2, in which a homozygous polymorphism in the coding region is present in around 13% of Caucasians. The functional significance of this variant is debated and recent studies suggest that it may have effects on neuronal cellular function independent of its deiodinase activity. Associations with osteo-arthritis and bipolar disorder have been reported, as well as psychological well-being on thyroid hormone and response to therapy. Thyroid hormone bioavailability the combination of low thyroid hormone levels and Thr92Ala homozygosity has also been associated with reduced IQ in children. Not all studies have replicated these effects and further well powered studies are required. Defining these effects more precisely should allow us to determine individually adjusted thresholds for initiating thyroid hormone therapy in order to derive net benefit as well as determining if there is any biological basis for the need for combination T4 and T3 therapy in selected individuals.