Nuclear receptors (NRs) are transcription factors whose activities are modulated by the binding of small lipophilic ligands. The liver X receptors (LXRs) are an important pair of mammalian NRs that regulate lipid metabolism upon binding to cholesterol metabolites called oxysterols. A recent report that LXR activity is also regulated by binding to glucose (Mitro et al., 2007) expands the potential role of LXR in metabolic sensing and gene regulation. However, the hydrophilic nature of glucose and its low affinity for LXR present a challenge to central dogma about the nature of the NR-ligand interaction.