Drug-induced adverse reactions (ADR) include any undesirable pharmacological effect that occurs following drug administration at therapeutic doses. The appearance of ADR significantly limits the use of drugs in as much as their clinical symptoms may range from very mild discomfort such as cutaneous rash, up to very severe, or even fatal tissue necrolysis such as the Stevens Johnson syndrome.One of the most frequently involved organ during ADR is the skin. Drug-induced cutaneous reactions (CDR) incidence is variable but they may appear in 2-3% of ambulatory patients, and it may increase to 10-15% when patients are hospitalized, or even be as high as 60% when co morbidity includes the presence of virus, bacteria, or parasites.Due to the fact that skin is one of the organs most frequently involved in ADR, in this work we analyze and propose a mechanism by which epidermal dendritic cells operating as the sentinels of the skin neuro-immune-endocrine system may contribute to CDR via either immunogenic or tolerogenic immune responses towards drugs, whenever they are administered topic or systemically.