1. In addition to its role in cellular metabolic activity, thyroid hormone (TH) is critically involved in growth, development, and function of the central nervous system. In the brain, as in other structures, TH is described to exert its major action by the binding of L-3,5,3'-triiodothyronine (T3), considered as the bioactive form of the hormone, to nuclear thyroid hormone receptors (TR) that function as ligand-dependent transcription factors. 2. The transcription of numerous brain genes was indeed shown to be positively or negatively regulated by TH, turning these TR-mediated effects one explanation for the physiological effects of TH. In this context, the knowledge from TR-knockout studies provides some surprising results, since neonatal hypothyroidism is associated to more significant abnormalities than is TR deficiency. Some (nonexclusive) hypotheses include a permissive effect of TH, allowing derepression of unliganded-TR effects and non-TR-mediated effects of the hormone, further emphasizing the importance of a controlled accessibility of neural cells to TH. 3. On the other hand, T3 was demonstrated to directly act not only on neuronal but also on glial cells proliferation and differentiation, contributing to the harmonious development of the brain. Interestingly, in addition to these direct actions on neuronal and glial cells, several lines of evidence, notably developped in our laboratory, point out the role of thyroid hormone in neuronal-glial interactions.