Adverse drug reactions (ADRs) are common and influence negatively the patient's therapeutic options. They recognize multiple pathogenic mechanisms, some of immunological origin, and the clinical manifestations involve several organs and systems, including skin and/or mucous membranes in 25-30% of patients. The identification of the trigger drug remains a medical challenge, mainly in poly-medicated patients. Anamnesis and clinical approach are crucial, but allergy work-up is the essential tool to confirm or exclude the causative role of the culprit drug. Besides in-vitro tests and drug provocation test, skin tests (ST) represent the cornerstone: patch test in delayed ADR, prick test in immediate ADR, and intradermal test in both. Nevertheless, ST are in continuous evolution and characterized by technical difficulties (concentration and vehicle) that can influence their value and specificity. In this article we review the indications and the rules in performing patch test, prick test, and intradermal test with the most commonly used drugs in Italy to determine the cause of a cutaneous and/or mucous ADR, precise the involved pathogenic mechanism, and provide a valid therapeutic alternative to the patient.