Corticosteroid-binding globulin (CBG) binds cortisol with high affinity, facilitating transport of cortisol in blood, although tissue-specific CBG–cortisol interactions have long been postulated. There are three heritable, human CBG gene mutations that can reduce CBG–cortisol binding affinity and/or reduce circulating CBG levels. In some families, fatigue and low blood pressure have been associated with affinity altering or CBG level reducing mutations. The limited numbers of reports raise the possibility of ascertainment bias as many cases presented with features suggesting cortisol deficiency. The recent description of a genetically CBG-deficient mouse listed fatigue, manifest as reduced activity levels, as part of the phenotype, which also included immune aberrations. Severe CBG mutations may produce fatigue, but one study suggests that these are a rare cause of idiopathic fatigue. A mechanism for the effect of CBG mutations on fatigue is not readily apparent because free cortisol levels are normal, although we speculate that CBG may have an effect on cortisol–brain transport.