Treatment of hypothyroidism involves the endogenous conversion of thyroxine (T4) to 3,5,3′-triiodothyronine (T3) and may not be optimal in some cases when based on T4 alone. In the current issue of the JCI, Jo et al. present results that explain the reduced enzymatic activity of a common genetic variant of the enzyme responsible for this conversion, type 2 deiodinase (DIO2). The authors further explore the functional consequences of this variant on brain T3 activity, endoplasmic reticulum stress in glial cells, and cognitive function. These findings have important implications for the clinical treatment of hypothyroidism and for susceptibility to other neurological and metabolic diseases.