Central hypothyroidism is a rare and heterogeneous disorder that is characterized by a defect in thyroid hormone secretion in an otherwise normal thyroid gland due to insufficient stimulation by TSH. The disease results from the abnormal function of the pituitary gland, the hypothalamus, or both. Moreover, central hypothyroidism can be isolated or combined with other pituitary hormone deficiencies, which are mostly acquired and are rarely congenital. The clinical manifestations of central hypothyroidism are usually milder than those observed in primary hypothyroidism. Obtaining a positive diagnosis for central hypothyroidism can be difficult from both a clinical and a biochemical perspective. The diagnosis of central hypothyroidism is based on low circulating levels of free T4 in the presence of low to normal TSH concentrations. The correct diagnosis of both acquired (also termed sporadic) and congenital (also termed genetic) central hypothyroidism can be hindered by methodological interference in free T4 or TSH measurements; routine utilization of total T4 or T3 measurements; concurrent systemic illness that is characterized by low levels of free T4 and normal TSH concentrations; the use of the sole TSH-reflex strategy, which is the measurement of the sole level of TSH, without free T4, if levels of TSH are in the normal range; and the diagnosis of congenital hypothyroidism based on TSH analysis without the concomitant measurement of serum levels of T4. In this Review, we discuss current knowledge of the causes of central hypothyroidism, emphasizing possible pitfalls in the diagnosis and treatment of this disorder.