Steroid and thyroid hormones, and vitamins A and D bind to nuclear receptors, which act as ligand-modulated transcription factors. In many cases, ligand-activated nuclear receptor binds to positively acting hormone response elements (p-HREs) to induce gene transcription. However, ligand-activated receptors also repress transcription of specific genes and several mechanisms that account for negative regulation have recently emerged. One major form of negative regulation is based on transcriptional interference between nuclear receptors and other transcription factors, such as AP-1. In this case, the liganded receptor prevents AP-1 or other positively acting transcription factors from fruitful interaction with the transcription initiation complex. A second form of negative regulation is based on binding of nuclear receptors to specialized negative HREs (n-HREs). Binding of unliganded receptor to such an element results in constitutive activation, which is terminated by the binding of ligand. While transcriptional interference with AP-1 has been described for many members of the nuclear receptor family, negative regulation through n-HREs so far has been shown only for one of the thyroid hormone receptors. However, this type of negative regulation is likely to be widespread.