There is increasing evidence that epigenetic regulation of gene expression plays a pivotal role in the orchestration of immune and allergic responses. Such regulatory mechanisms have potentially important implications for the acquisition of sensitization to chemical and drug allergens; and in determining the vigor, characteristics, and longevity of allergic responses. Importantly, the discovery of long-lasting epigenetic alterations in specific immunoregulatory genes provides a mechanistic basis for immune cell memory, and thereby the potential of chemical allergens to influence the subsequent orientation of the adaptive immune system. In this article, we consider the implications of epigenetic mechanisms for the development of sensitization to chemical and drug allergens and the form that allergic reactions will take.