Thyroid hormone (T(3)) influences cell proliferation, death and differentiation during development of the central nervous system (CNS). Hormone action is mediated by T(3) receptors (TR) of which there are two subtypes, TRalpha and TRbeta. Specific roles for TR subtypes in CNS development are poorly understood. We analyzed involvement of TRalpha and TRbeta in neural cell proliferation during metamorphosis of Xenopus laevis. Cell proliferation in the ventricular/subventricular neurogenic zones of the tadpole brain increased dramatically during metamorphosis. This increase was dependent on T(3) until mid-prometamorphosis, after which cell proliferation decreased and became refractory to T(3). Using double labeling fluorescent histochemistry with confocal microscopy we found TRalpha expressed throughout the tadpole brain, with strongest expression in proliferating cells. By contrast, TRbeta was expressed predominantly outside of neurogenic zones. To corroborate the histochemical results we transfected living tadpole brain with a Xenopus TRbeta promoter-EGFP plasmid and found that most EGFP expressing cells were not dividing. Lastly, treatment with the TRalpha selective agonist CO23 increased brain cell proliferation; whereas, treatment with the TRbeta-selective agonists GC1 or GC24 did not. Our findings support the view that T(3) acts to induce cell proliferation in the tadpole brain predominantly, if not exclusively, via TRalpha.