The timing of oligodendrocyte differentiation is thought to depend on both intracellular mechanisms and extracellular signals. Thyroid hormone (TH) helps control this timing both in vitro and in vivo, but it is still uncertain how it does so. TH acts through nuclear receptors that are encoded by two genes, TRα and TRβ. Previous studies suggested that TRβ receptors may mediate the effect of TH on oligodendrocyte precursor cells (OPCs). Consistent with this possibility, we show here that overexpression of TRβ1 promotes precocious oligodendrocyte differentiation, whereas expression of two dominant-negative forms of TRβ1 greatly delays differentiation. Surprisingly, however, we find that postnatal TRβ−/− mice have a normal number of oligodendrocytes in their optic nerves and that TRβ−/− OPCs stop dividing and differentiate normally in response to TH in vitro. Moreover, we find that OPCs do not express TRβ1 or TRβ2 mRNAs, whereas they do express TRα1 and TRα2 mRNAs. These findings suggest that α receptors mediate the effect of TH on the timing of oligodendrocyte differentiation. We also show that TRα2 mRNA, which encodes a dominant-negative form of TRα, decreases as OPCs proliferate in vitro and in vivo. This decrease may help control when oligodendrocyte precursors differentiate.