Diseases such as chronic obstructive pulmonary disease and lung cancer caused by cigarette smoke affect millions of people worldwide. The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor that influences responses to certain environmental pollutants such as tobacco smoke. However, the physiological function(s) of the AhR is unknown. Herein, we propose that the physiologic role of the AhR is to limit inflammation. We show that lung fibroblasts from AhR(-/-) mice produce a heightened inflammatory response to cigarette smoke, typified by increased levels of cyclooxygenase-2 (Cox-2) and prostaglandins (PG), when compared to wild type (AhR(+/+)) fibroblasts. This response was dependent on AhR expression, as transient transfection of an AhR expression plasmid into AhR(-/-) fibroblasts significantly attenuated the smoke-induced Cox-2 and PG production, confirming the anti-inflammatory role of the AhR. The AhR can interact with NF-kappaB. However, the heightened inflammatory response observed in AhR(-/-) fibroblasts was not the result of NF-kappaB (p50/p65) activation. Instead, it was coupled with a loss of the NF-kappaB family member RelB in AhR(-/-) fibroblasts. Taken together, these studies provide compelling evidence that AhR expression limits pro-inflammatory Cox-2 and PG production by maintaining RelB expression. The association between RelB and AhR may represent a new therapeutic and more selective target with which to combat inflammation-associated diseases.