LXRα is a nuclear receptor that defines a distinct retinoid response pathway. This study identifies LXRα as a new retinoid response pathway through which 9-cis retinoic acid (9cRA) activates transcription in the presence of LXRα. LXRα shows a specific pattern of expression in visceral organs, restricting the response to certain tissues. Retinoid trans-activation occurs selectively on a distinct response element termed an LXRE. Neither RXR homodimers nor RXR/RAR heterodimers can substitute for LXRα in mediating this retinoid response. The retinoid response on the LXRE is due to a unique interaction between LXRα and endogenous RXR, which makes RXR competent to respond to retinoids. This interaction shifts RXR from a silent, DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXREs. The study reports the identification of an orphan member of the nuclear receptor superfamily, LXRα. In the presence of 9cRA, LXRα is required for trans-activation through a distinct retinoid response element. The data indicate that the LXRα response to retinoid is attributable to its unique interaction with endogenous RXR in cells. This interaction permits RXR to work as an active, ligand-binding heterodimeric partner. These results demonstrate the ability of LXRα to function as a tissue-specific mediator of a novel 9cRA response pathway. The study also shows that LXRα forms a functional heterodimer with RXRα. The data suggest that LXRα is not directly bound and activated by retinoids but instead is an obligatory heterodimeric partner of endogenous RXR. The results distinguish the human LXRα as a novel mediator of retinoid action. The study further demonstrates that the LXR/RXR heterodimer binds and activates through the LXRE. The LXRE is a novel DR4 retinoid response element. The study concludes that LXRα defines a third 9cRA response pathway in which RXR participates as the active ligand-binding partner. The LXR/RXR heterodimer responds to retinoid through a specific DR4-like element (the LXRE). Unlike the RXR response on a DR1 element, the LXR/RXR response is uniquely sensitive to 9cRA and can function potently in the presence of the low levels of endogenous RXR in the cell. The study also highlights the importance of RXR in retinoid signaling and the role of LXRα as a tissue-specific cofactor that permits RXR to function as a potent 9cRA receptor with a distinct target gene specificity.LXRα is a nuclear receptor that defines a distinct retinoid response pathway. This study identifies LXRα as a new retinoid response pathway through which 9-cis retinoic acid (9cRA) activates transcription in the presence of LXRα. LXRα shows a specific pattern of expression in visceral organs, restricting the response to certain tissues. Retinoid trans-activation occurs selectively on a distinct response element termed an LXRE. Neither RXR homodimers nor RXR/RAR heterodimers can substitute for LXRα in mediating this retinoid response. The retinoid response on the LXRE is due to a unique interaction between LXRα and endogenous RXR, which makes RXR competent to respond to retinoids. This interaction shifts RXR from a silent, DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXREs. The study reports the identification of an orphan member of the nuclear receptor superfamily, LXRα. In the presence of 9cRA, LXRα is required for trans-activation through a distinct retinoid response element. The data indicate that the LXRα response to retinoid is attributable to its unique interaction with endogenous RXR in cells. This interaction permits RXR to work as an active, ligand-binding heterodimeric partner. These results demonstrate the ability of LXRα to function as a tissue-specific mediator of a novel 9cRA response pathway. The study also shows that LXRα forms a functional heterodimer with RXRα. The data suggest that LXRα is not directly bound and activated by retinoids but instead is an obligatory heterodimeric partner of endogenous RXR. The results distinguish the human LXRα as a novel mediator of retinoid action. The study further demonstrates that the LXR/RXR heterodimer binds and activates through the LXRE. The LXRE is a novel DR4 retinoid response element. The study concludes that LXRα defines a third 9cRA response pathway in which RXR participates as the active ligand-binding partner. The LXR/RXR heterodimer responds to retinoid through a specific DR4-like element (the LXRE). Unlike the RXR response on a DR1 element, the LXR/RXR response is uniquely sensitive to 9cRA and can function potently in the presence of the low levels of endogenous RXR in the cell. The study also highlights the importance of RXR in retinoid signaling and the role of LXRα as a tissue-specific cofactor that permits RXR to function as a potent 9cRA receptor with a distinct target gene specificity.