Sustained transcriptional activation of the aryl hydrocarbon receptor (AhR) promotes tumour growth and impairs the immune defence, at least for cutaneous melanoma and glioma. AhR ligands are produced by the tumour microenvironment (TME) and by the tumour itself (intracrine). The recent identification of interleukin-4-induced-1 (IL4I1), a parallel pathway to indoleamine 2 3-dioxygenase 1 (IDO1)/tryptophan 2, 3-dioxygenase (TDO), and its ability to generate AhR ligands, confirms that a complete inhibition of AhR ligand production might be difficult to reach. Here, we have focused on recent discoveries explaining the large varieties of AhR ligands and the functional consequences in terms of cancer cell plasticity and consecutive therapy resistance. We also examined therapeutic strategies targeting the AhR signalling pathway and their possible adverse effects. Since the end of 2019, two phase I clinical trials have investigated the ability of the AhR antagonist to ‘reset’the immune system and re-sensitize the cancer cells to therapies by preventing their dedifferentiation.