Thyroid hormone (TH)-regulated gene expression is mainly mediated by TH binding to nuclear thyroid hormone receptors (TRs). Despite extensive studies in mammalian cell lines that show that phosphorylation signaling pathways are important in TH action, little is known about their roles on TH signaling in vivo during development. Anuran metamorphosis is a postembryonic process that is absolutely dependent upon TH and tadpole tail resorption can be precociously induced by exogenous administration of 3,5,3′-triiodothyronine (T3). We demonstrate that genistein (a major isoflavone in soy products and tyrosine kinase inhibitor) and the PKC inhibitor (H7) prevent T3-induced regression of the Rana catesbeiana tadpole tail. T3-induced protein kinase C tyrosine phosphorylation and kinase activity are inhibited by genistein while T3-induced up-regulation of TRβ mRNA, but not TRα mRNA, is significantly attenuated, most likely through inhibition of T3-dependent phosphorylation of the TRα protein. This phosphorylation may be modulated through PKC. These data demonstrate that T3 signaling in the context of normal cells in vivo includes phosphorylation as an important factor in establishing T3-dependent tail regression during development. Developmental Dynamics 236:777–790, 2007. © 2007 Wiley-Liss, Inc.