Allergic reactions to antibiotics have raised considerable concerns, and are still underevaluated. It is a daily problem for general practitioners and allergologists. Their clinical manifestations are numerous, ranging from mild maculo-papular eruptions to sometimes deadly anaphylactic shocks or epidermal necrolisis. Atopy is not a risk factor, but concomitant viral infections, including Epstein-Barr virus and HIV infections are. HIV-infected patients indeed suffer more frequently from drug-induced hypersensitivity reactions than immunocompetent subjects or even non-HIV immunodeficient patients. We are lacking clinical and biological tools and the available ones still need to be validated. However, a precise diagnosis is required in order to set up prevention measures. In some cases, graded challenges (desensitization when an IgE mechanism is involved) is possible and efficacious (quinolones for cystic fibrosis, sulfonamides for HIV-infected patients).