Thyroid hormones are a critical regulator of mammalian physiology. Much of their action is due to effects in the nucleus where T engages thyroid hormone receptor isoforms to mediate its effects. In order to function properly the TR isoforms must be recruited to regulatory sequences within genes that they up-regulate. On these positive regulated target genes the TR can activate or repress depending upon whether the receptor is bound to T or not and the type of co-regulatory proteins present in that cell type. In contrast to T mediated activation, the mechanism by which the TR represses transcription in the presence of T remains unclear. Herein we will review the components of the transcriptional response to T within the nucleus and attempt to highlight the outstanding questions in the field.