Abstract: Contact allergens are small reactive chemicals. They cause allergic contact dermatitis (ACD) by activating the innate and adaptive immune system. Contact allergens are very peculiar because of their built-in autoadjuvanticity that allows them to trigger sterile inflammation following skin penetration. The innate inflammatory response involves the triggering of pattern recognition receptors either by direct chemical interaction with such receptors or by induction of endogenous activators. I discuss here the recent findings regarding prevalence and predisposition, the identification of innate immune and stress response mechanisms relevant for sensitization and the orchestration of the innate and adaptive immune response to contact allergens. Despite still significant gaps of knowledge, recent advances in our understanding of the immunopathogenesis of ACD can now be used for the development of causative treatment strategies and of in vitro alternatives to animal testing for the identification of contact allergens in immunotoxicology.