The aryl hydrocarbon receptor (AhR), discovered 46 years ago, is a transcript factor member of the basic helix-loop-helix Per-ARNT-SIM (bHLH-PAS) family deeply implicated in health and diseases, and is traditionally associated with the metabolism of xenobiotic ligands. Recently, multiple and structurally diverse ingredients including amino acid metabolites, polyphenols, flavonoids, polyhydroxyalkanoates, polychlorinated biphenyls, and, triarylmethanes have been evaluated as AhR potential ligands, and there is increasing attention on AhR as an appealing target in various cancers, autoimmune disorders, inflammatory bowel diseases, rheumatoid arthritis and multiple sclerosis. Herein, this review focuses on the recent advances of AhR, covering articles published between 2002 and 2022. It summarizes the structure of AhR, regulation of the AhR pathway, physiological role, and AhR ligands, highlighting the vast opportunities and challenges for targeting drug development of AhR.