At present, cephalosporins represent one of the most prescribed classes of antibiotics. Although allergic reactions have been estimated to be infrequent, the number of reactions to cephalosporins is increasing due to their wide use. Cross-reactivity with penicillins has mainly been evaluated in patients with penicillin allergy. It is higher between first- and second-generation cephalosporins with the same or similar side chain than between cephalosporins with different side chains. Unlike penicillins, cephalosporin haptens or determinants have not been defined, and therefore the diagnosis is complicated. Nevertheless, skin tests with cephalosporins are useful in the evaluation of several allergic reactions. Although more studies are necessary, a negative result in skin testing to penicillin and cephalosporins with different side chains seems to be a good predictor of tolerance, and could be used in select cases.