To investigate the transcriptional program underscoring cell proliferation induced by thyroid hormone (T3), we used complementary DNA mircroarrays to survey the temporal expression profiles of 4,400 genes in a classical T3 model. Of 352 responsive genes identified, 77% had not previously been reported to be transcriptionally or functionally modulated by T3, thereby increasing the number of reported T3 genes by approximately 250%. Partitioning the genes into functional classes revealed the activation of multiple pathways (including those for glucose metabolism, biosynthesis, transcriptional regulation, protein degradation and stress response and detoxification) in T3-induced cell proliferation. Clustering the genes by temporal expression patterns and expression timing provided further insight into the dynamics of T3 response pathways. Of particular significance was the finding that T3 rapidly repressed the expression of a host of key regulators of the tumor-promoting Wnt signaling pathway and the transcriptional activity of the β-catenin-TCF complex. Furthermore, activation of Wnt signaling led to inhibition of T3-mediated cell proliferation. These results indicate that cell proliferation induced by thyroid hormone is accompanied by a complex, coordinated transcriptional reprogramming of many genes in different pathways and that early silencing of the Wnt pathway is critical to this event.