The popularity of “allergy to penicillin” is an unsettling and expensive phenomenon. It results from the confusion of concepts: (1) hypersensitivity; (2) sensitisation; (3) allergy. It leads to unjustified exclusion from therapy of all β-lactam antibiotics and replacement with antibiotics of other groups that turn out to be more expensive and more toxic. According to contemporary European and American guidelines, the recognition of a specific hypersensitivity to an antibiotic should precede the diagnosis of its pathomechanism. Hence the particular importance of estimating the probability of causality between events that consist of: (1) the application/use of a suspect antibiotic; (2) disturbing symptoms associated with a hypersensitivity reaction. Identification of the factor/substance triggering such symptoms is synonymous with the recognition of a specific hypersensitivity reaction. The next step is identification of IgE-dependent or IgE-independent (allergic hypersensitivity) or other (non-allergic hypersensitivity) reaction mechanism. Suspecting allergic hypersensitivity, we refer to sensitization of detection techniques. The limited sensitivity and specificity mean that in practice we rely on tests for the detection of IgE-dependent allergens for penicillins and cephalosporins. The estimated predictable values of skin tests mean that by identifying IgE-dependent allergic hypersensitivity to penicillin or cephalosporin, we select a safe alternative antibiotic. This is facilitated by the algorithms presented in this paper. An alternative to penicillin or cephalosporin usually is another penicillin, cephalosporin or other β-lactam antibiotic. It is not less important to improve the quality of the diagnosis of IgE-independent reactions and other adverse B-type reactions to β-lactam antibiotics and other groups. Decisions relating to the selection of a safe alternative medicine, or the so-called desensitisation remain at the discretion of the attending physician. We believe that the introduction of proposed procedures in several cooperating domestic centers will contribute to the improvement of the quality of diagnoses and the security of procedures implemented.