Nuclear receptors and the AP-1 transcription factors (homodimers and heterodimers of members of the Jun/Fos/ATF/families) mutually influence their activities, positively and negatively. Mutual negative interference is of practical importance as it can be exploited for therapy of human diseases. Since the discovery of cross-modulation, many reports, seemingly not always compatible, have appeared. Recent experimental evidence may help to develop a model for this interesting transcription factor interaction that satisfies most observations. Transactivation and transrepression (as one facet o f cross-modulation) are separable activities o f the nuclear receptors. The modulating property appears to be exerted by nuclear receptor monomers. These conclusions are supported by point mutations in the glucocorticoid receptor and by the specific inhibitory effects of ligand analogues on transactivation only. These pilot experiments make a search for ligands that enhance the cross-modulatory function without triggering transactivation very promising.