Target alteration underlies resistance to beta-lactam antibiotics in both Staphylococcus species and Streptococcus pneumoniae. The penicillin-binding protein (PBP) targets in penicillin-resistant strains of S. pneumoniae are modified, low-binding-affinity versions of the native PBPs. Multiple PBP targets may be modified by transformation and homologous recombination with DNA from PBP genes of viridans streptococci. The level of resistance is determined by how many and to what extent targets are modified. In contrast, methicillin resistance in staphylococci is due to expression of PBP 2a, a novel, low-affinity PBP for which there is no homologue in methicillin-susceptible strains. PBP 2a is encoded by mecA, a highly conserved gene most likely acquired by a rare transposition from Staphylococcus sciuri or a closely related ancestor. Expression of resistance can be highly variable, but this seems not to be determined by PBP modifications. Several non-PBP factors are required for high-level resistance.