Beta-lactam antibiotics (BLs) are the most frequent cause of hypersensitivity reactions mediated by specific immunological mechanisms, with two main types, IgE reactions or T-cell-dependent responses. From a practical point of view, these reactions can be classified into immediate, for those appearing within 1 h after drug intake, and non-immediate, for those appearing at least 1 h after and usually within 24 h of BL administration. The clinical symptoms differ according to this classification. Urticaria and anaphylaxis are the most frequently recorded symptoms in immediate reactions and maculopapular exanthema and delayed urticaria in non-immediate reactions. Although the exact diagnostic approach differs depending on the underlying mechanism, it is based on the performance of skin testing, laboratory tests, and drug provocation tests.T cells are a key factor in all types of hypersensitivity reactions to BLs, regulating both IgE production or acting as effector cells, with a different profile of cytokine production. A Th1 pattern is observed in both CD4(+) and CD8(+) peripheral T cells in non-immediate reactions, whereas a Th2 pattern is expressed in CD4(+) T cells in immediate reactions.