The data presented in this review confirm that penicillin continues to be the most well defined model for studying drug allergy. The identification of new specificities has improved the understanding of allergy to penicillins, and different well defined subgroups now exist. The capacity of humans to respond to unique penicillin determinants has shown that although penicillin is a very small molecule it can be recognized in different ways by different IgE antibodies. These well defined models have left open the possibility that other betalactams can also induce specific reactions which implies that for diagnostic purposes, in addition to classical determinants, others are required for in vitro and/or in vivo evaluation. When the different subgroups now recognized are compared, not only are there differences in the manner of hapten recognition but also in the evolution of the natural sensitivity and in the capacity for recognizing other structures. The recognition of betalactams by T cells is also important and a number of studies have shown that subjects respond specifically to some aminopenicillins or cephalosporins with good tolerance to benzylpenicillin. The confirmation that these responses can be a T-cell-mediated reaction have been reported not only in vitro by the generation of T cell lines and T cell clones but also in vivo doing skin biopsies in subjects who have developed different types of delayed cutaneous reactions [44]. More studies are needed to determine the structure of T cell epitopes and this will help for a better understanding of both the IgE and IgG-mediated reactions.