The use of β-lactam antibiotics to treat infections caused by Staphylococcus aureus has been severely compromised by the acquisition by horizontal gene transfer of a gene that encodes the β-lactam-insensitive penicillin-binding protein PBP2a. This allows methicillin-resistant S. aureus (MRSA) to proliferate in the presence of β-lactam antibiotics. Paradoxically the dependence on PBP2a for the essential transpeptidase activity in cell wall peptidoglycan biosynthesis is the ‘Achilles heel’ of MRSA. Compounds that disrupt the divisome, wall teichoic acid, and functional membrane microdomains act synergistically with β-lactams against MRSA. These include drugs such as statins that are widely used in human medicine. The antibiotics vancomycin and daptomycin are also synergistic with β-lactams, and combinations have been employed to treat persistent MRSA infections. An additional benefit of exposing MRSA to β-lactams could be a reduction in virulence mediated by interfering with the global regulator Agr. The mechanistic basis of synergy is discussed, and the possibility that β-lactams can be resurrected to combat MRSA infections is explored. While the penicillin-binding protein PBP2a allows MRSA to synthesize peptidoglycan in the presence of β-lactam antibiotics, PBP2a is also its ‘Achilles heel’. Compounds that interfere with the stability of PBP2a by inhibiting functional membrane microdomains, wall teichoic acid, or the PrsA chaperone render MRSA susceptible to β-lactam antibiotics. Compounds that interfere with protein secretion or the divisome act synergistically with β-lactam antibiotics. Daptomycin acts synergistically with β-lactams that target PBP1 and have been used together to treat persistent MRSA infections. Daptomycin-resistant MRSA strains are sensitized to β-lactams that target PBP2 because of failure to link to the membrane the PrsA chaperone lipoprotein needed for PBP2a stability. β-Lactams can reduce the virulence of MRSA by making it more susceptible to host antimicrobial peptides and by reducing toxin expression.