Small molecules, used as drugs, can induce immune reactions by binding covalently as haptens to a carrier protein, which is thereby modified and immunogenic. In addition, drugs bind to proteins via hydrogen bonds, electrostatic force, and van der Waals forces, and may directly interact with immune receptors such as T cell receptors or major histocompatibility complex molecules (pharmacologic interaction with immune receptors, so-called p-i concept). Even this noncovalent interaction may stimulate T cells. The ensuing immune response based on hapten-peptide presentation or direct drug-receptor interaction results in many distinct clinical situations. Based on progress in T cell immunology, this heterogeneity of T cell reaction is now also reflected in a subclassification of type IVa to IVd reactions.