Virus infections and T cell-mediated drug hypersensitivity reactions (DHR) can influence each other. In most instances, systemic virus infections appear first. They may prime the reactivity to drugs in two ways: First, by virus-induced second signals: certain drugs like β-lactam antibiotics are haptens and covalently bind to various soluble and tissue proteins, thereby forming novel antigens. Under homeostatic conditions, these neo-antigens do not induce an immune reaction, probably because co-stimulation is missing. During a virus infection, the hapten-modified peptides are presented in an immune-stimulatory environment with co-stimulation. A drug-specific immune reaction may develop and manifest as exanthema. Second, by increased pharmacological interactions with immune receptors (p-i) : drugs tend to bind to proteins and may even bind to immune receptors. In the absence of viral infections, this low affine binding may be insufficient to elicit T cell activation. During a viral infection immune receptors are more abundantly expressed and allow more interactions to occur. This increases the overall avidity of p-i reactions and may even be sufficient for T cell activation and symptoms. There is a situation, where the virus-DHR sequence of events is inversed: in drug reaction with eosinophilia and systemic symptoms (DRESS), a severe DHR can precede reactivation and viremia of various herpes viruses. One could explain this phenomenon by the massive p-i mediated immune stimulation during acute DRESS, which coincidentally acvitates many herpes virus-specific T cells. Through p-i stimulation, they develop a cytotoxic activity with killing of herpes peptide-expressing cells and release of herpes viruses. These concepts could explain the often transient nature of DHR occurring during viral infections and the often asymptomatic herpes-virus viraemia after DRESS.