Metabolic NRs (FXR, LXR, PPAR, PXR, and HNF4α) are presumed to sense and respond to small lipophilic ligands (agonists and antagonists) and metabolic intermediates (modulators), as a monomer, a homodimer, or a heterodimer (usually with RXR). Upon binding to ligands or other modulators, these NRs bind to their cognate sequence-specific NRRE in regulatory regions of their target genes. NR DBD contributes to response element selection, whereas LBD contributes to dimerization and determines ligand-regulated interactions with coregulators. The orphan nuclear hormone receptor SHP interacts with a number of metabolic NRs and functions as a major transcription repressor that controls liver metabolism. Many NRs have well-characterized natural ligands and synthetic drugs, but the ligand for some of the NRs such as SHP is yet unknown. Discovery of more specific and new NR-targeting drugs will offer promise for better treatment of liver disorders in which NRs play a central role. Abbreviations: DBD, DNA binding domain; FXR, farnesoid X receptor; HNF4α, hepatic nuclear factor-4-alpha; LBD, ligand-binding domain; LXR, liver X receptor; NR, nuclear receptor; NRRE, nuclear receptor response element; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; RXR, retinoid X receptor; SHP, small heterodimer partner.