The aryl hydrocarbon receptor (AhR) mediates nearly all studied adverse effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and many related compounds. Binding of TCDD or related ligands to AhR is the key initiating event in downstream biochemical responses. The binding affinity of AhR for TCDD is specific to species and strain, and studies of human AhR demonstrate binding affinities approximately an order of magnitude or more lower than those observed in the most sensitive laboratory strains and species. Molecular genetic studies confirmed that human AhR shares key mutations with the DBA mouse strain that result in an "impaired" AhR (with respect to TCDD binding and responsiveness). Despite a number of polymorphisms in human AhR, the key "DBA-type" mutations appear to be a constant feature of the human AhR, and no polymorphisms have been identified that compensate for the impaired binding function conferred by these mutations. Consistent with the impaired binding status of the human AhR, human cells have consistently required approximately 10-fold higher concentrations of TCDD in vitro than rodent cells to respond with enzyme induction. Recent studies of in vivo enzyme induction-related endpoints in human populations with moderately and highly increased TCDD body burdens detected no relationship between these endpoints and TCDD body burdens at body-burden levels up to 250 ng TEQ/kg body weight, or approximately 25 times above the upper range of current general population background body burdens, while marked elevations in enzyme activity were observed in persons with body burdens above 750 ng TEQ/kg. In contrast, the more sensitive laboratory rodent strains and species exposed to TCDD exhibit significant enzyme induction at body burdens below 50 ng/kg. These interspecies data on the most sensitive and best understood response to binding of TCDD and related compounds to the AhR are consistent with the binding affinity and molecular structure data and support the hypothesis that the human AhR is less functional than the AhR of the more sensitive laboratory animals at a molecular level. Quantitative risk assessments involving interspecies extrapolation from sensitive laboratory species and strains should take these fundamental differences into account when margins of exposure and safety factors are considered.