Nuclear receptors function as ligand-regulated transcription factors and modulate the expression of sets of genes in response to varying concentrations of ligands. The ligand modulators can be endogenous metabolites that function as hormones, or they can be exogenous substances, such as pharmaceutical agents or environmental substances of natural or man-made origin, which in some cases can cause endocrine disruption. Ligands modulate nuclear receptor activity by binding to their ligand-binding domains and stabilizing conformations that lead either to transcriptional activation or repression. The ligand-binding pocket is somewhat flexible, and binding affinities can be measured over a 10-million-fold range (i.e., with equilibrium dissociation constant values ranging from ca. 0.01 nM to 100 μM). Thus, it is not surprising that by binding a large variety of structures, some nuclear receptors can appear to be promiscuous; however, when affinity is considered, the binding patterns are more restricted. The spectrum of ligands that bind to the estrogen receptor has been most thoroughly investigated. Those from natural sources include natural products in food, such as soy isoflavones and whole grain lignans, as well as microbial products and components from wood. Aside from pharmaceuticals, man-made estrogen ligands can be found in industrial products, such as alkyl phenols from nonionic detergents, bisphenols from plastics, indicator dye impurities, polymer chemicals, and chlorinated aromatics and pesticides. Exogenous ligands are also known for the androgen and progesterone receptors. While it is possible that endocrine disruption can result from exogenous chemicals acting directly as ligands for the nuclear receptors, endocrine disruption needs to be considered in the broader context; thus, compounds also need to be assessed for their effects at other levels, such as on endogenous hormone production, transport, metabolism, and clearance, and at points in signal transduction cascades that are beyond the ligand-receptor interaction.