Various haptens trigger innate immune pathways and/or induce cytotoxicity as a part of sensitization. Adam et al. decipher in vitro the mechanisms by which chromium(VI) induces inflammation, the likely prerequisites for toxicity, sensitization, and allergic contact dermatitis against chromium(VI). Importantly, and in line with other observations, chromium(VI), but not chromium(III) (or Ni(II)), induces mitochondrial reactive oxygen species accumulation. Mitochondrial reactive oxygen species in turn activate the NLRP3 inflammasome, allowing increased IL-1 beta processing and secretion, which likely underlies both chromium(VI)-induced cutaneous toxicity and sensitization. Interrupting this mechanism, perhaps with reducing agents or inhibitors of the NLRP3/IL-1 axis, may be a new option to prevent occupational chromium toxicity and allergy.