Streptococcus pneumoniae and Group A Streptococci are frequent colonizers and major causative agents of disease in the upper respiratory tract of humans. In spite of the immense and common selective pressure of beta-lactam antibiotics against both of these bacterial species during the last four to five decades, penicillin-resistant strains of group A streptococci have not been described in the clinical literature as of 1994. This is particularly puzzling since penicillin-resistant mutants of this bacterium have been isolated repeatedly in the laboratory and such mutants carry altered penicillin-binding proteins (PBPs) with reduced drug affinities, i.e., a basic mechanism identical to the one seen in penicillin-resistant isolates of Streptococcus pneumoniae that have emerged in large numbers and at numerous locations and have spread explosively all over the globe by the beginning of the 1990s. The reasons for this contrasting situation are not clear. In Streptococcus pneumoniae the resistance mechanism to penicillin appears to originate in recombinational events between ancestral pneumococcal cells and as yet unidentified extra species DNA donors and probably involves the process of genetic transformation for which this bacterium has a remarkable hormonally controlled mechanism. The integration of foreign DNA sequences in the pneumococcal PBP genes leads to the remodeling of at least four of the five PBPs that change in their kinetic properties and increase in the penicillin resistance level of the bacteria also seems to involve increased production of the low-affinity binding proteins.