Nuclear receptors are a superfamily of transcription factors regulated by a wide range of lipids that include phospholipids, fatty acids, heme-based metabolites and cholesterol-based steroids. Encoded as classic two-domain modular transcription factors, nuclear receptors possess a DNA-binding domain (DBD) and a lipid ligand-binding domain (LBD) containing a transcriptional activation function. Decades of structural studies on the isolated LBDs of nuclear receptors established that lipid-ligand binding allosterically regulates the conformation of the LBD, regulating transcriptional coregulator recruitment and thus nuclear receptor function. These structural studies have aided development of several FDA-approved drugs, highlighting the importance of understanding the structure-function relationships between lipids and nuclear receptors. However, there are few published descriptions of full-length nuclear receptor structure, and even fewer descriptions of how lipids might allosterically regulate full length structure. Here, we examine multi-domain interactions based on nuclear receptor structures for PPARγ (NR1C3), RXRα (NR2B1), LXRβ (NR1H2), RARβ (NR1B2), VDR (NR1I1), HNF4α (NR2A1), ERα (NR3A1), EcR (NR1H1) and LRH-1 (NR5A2), evaluating the potential of interdomain interfaces within these nuclear receptors to act as inducible sites of allosteric regulation by lipids and other small molecules.