The aryl hydrocarbon receptor (AhR) is a highly evolutionary conserved, ligand-activated transcription factor that is best known to mediate the toxicities of dioxins and dioxin-like compounds. Phenotype of AhR-null mice, together with the recent discovery of a variety of endogenous and plant-derived ligands, point to the integral roles of AhR in normal cell physiology, in addition to its roles in sensing the environmental chemicals. Here, we summarize the current knowledge about AhR signaling pathways, its ligands and AhR-mediated effects on cell specialization, host defense and detoxification. AhR-mediated health effects particularly in liver, immune, and nervous systems, as well as in tumorgenesis are discussed. Dioxin-initiated embryotoxicity and immunosuppressive effects in fish and birds are reviewed. Recent data demonstrate that AhR is a convergence point of multiple signaling pathways that inform the cell of its external and internal environments. As such, AhR pathway is a promising potential target for therapeutics targeting nervous, liver, and autoimmune diseases through AhR ligand-mediated interventions and other perturbations of AhR signaling. Additionally, using available laboratory data obtained on animal models, AhR-centered adverse outcome pathway analysis is useful in reexamining known and potential adverse outcomes of specific or mixed compounds on wildlife.