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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor originally identified as the target mediating the toxic effects of environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and dioxins. For years, AHR activation was actively avoided during drug development. However, the AHR was later identified as an important physiological regulator of the immune response. These findings triggered a paradigm shift that resulted in identification of the AHR as a regulator of both innate and adaptive immunity and outlined a pathway for its modulation by the diet, commensal flora and metabolism in the context of autoimmunity, cancer and infection. Moreover, the AHR was revealed as a candidate target for the therapeutic modulation of the immune response. Indeed, the first AHR-activating drug (tapinarof) was recently approved for the treatment of psoriasis. Clinical trials are underway to evaluate the effects of tapinarof and other AHR-targeting therapeutics in inflammatory diseases, cancer and infections. This Review outlines the molecular mechanism of AHR action, and describes how it regulates the immune response. We also discuss links to disease and AHR-targeting therapeutics that have been tested in past and ongoing clinical trials.