LXR is an orphan nuclear receptor that confers retinoid responsiveness to the retinoid X receptor (RXR) by its interaction on a specific response element called an LXRE. To understand the mechanism of this response, three characteristics were identified that are crucial to activation of the RXR-LXR complex. First, the orientation of the RXR-LXR heterodimer on DNA indicates that as the ligand-binding partner, RXR occupies the 5' half-site of the response element. Next, the sequence specificity of the LXRE was determined in order to identify residues required for retinoid activation of the heterodimer. Remarkably, subtle changes in the nucleotide sequence of the LXRE half-sites that do not substantially alter DNA binding of the RXR-LXR heterodimer have a significant effect on the ability of the complex to be activated by ligand. Finally, we characterized the contributions of the activation domains of each receptor to the trans-activation potential of the RXR-LXR heterodimer. Surprisingly, our results show that only the activation domain of LXR is required for retinoid activation. Taken together, these results demonstrate the existence of a unique form of communication between heterodimer partners in which the activation potential of one receptor (LXR) is enabled by ligand binding to its partner (RXR). Furthermore, we conclude that RXR ligand activation potential is not dictated solely by its position on DNA, but is influenced by other factors such as the receptor partner and sequence of the response element.