Allergic reactions to drugs are a matter of great concern, both for patients and health care professionals. The diagnosis is primarily based on a clinical history and in vivo tests, but they have some significant limitations in a range of clinical situations. This review presents currently available in vitro methods for the identification of the culprit drug in drug-induced immediate reactions (specific IgE determination, basophil activation test), T-cell-mediated drug allergy (lymphocyte transformation test, enzyme-linked immunosorbent spot assay, cell activation markers and cytokine release) and in nonallergic hypersensitivity to nonsteroidal anti-inflammatory drugs. Perspectives for further improvement of the in vitro diagnosis of drug allergy are also discussed.