Alteration of PBPs has proved an effective way for gram-positive bacteria to become resistant to beta-lactams. The gram-positive species have not been able to use decreased permeability or synthesis of novel beta-lactamases to overcome the advances by medicinal chemists. Nonetheless, altered PBPs have proved to be a formidable form of resistance for staphylococci, enterococci, and even some S. pneumoniae. Although isolated examples of resistance of gram-negative species to beta-lactams have been seen for E. coli, Serratia, or P. aeruginosa, in general this form of resistance has not been used by the gram-negative species except by N. gonorrhoeae. Conversely gram-negative bacteria have used beta-lactamases as an effective weapon to overcome the advances in medical chemistry that have provided beta-lactamase inhibitors and structurally stable cephalosporins, monobactams, and carbapenems. Derepression or induction of beta-lactamases has provided species such as E. cloacae and P. aeruginosa the ability to resist destruction by new cephalosporins. The original concept of beta-lactamase as a trap or sponge has been shown to be inaccurate, and we realize that the high concentration of beta-lactamase in the periplasmic space combined with a decreased or slow entry of the beta-lactam allows an efficient acylation of the so-called stable cephalosporins with hydrolysis of these compounds. Although the PBPs and beta-lactamases are clear problems, there is the potential for future modification of beta-lactam structures to increase affinity to PBPs and decrease beta-lactamase affinity. Bacterial populations do have the ability to create transferable resistance even to extended spectrum beta-lactams. It will be necessary to carefully monitor the development of resistance to new beta-lactams. However, advances in the chemistry of beta-lactams should offer solutions to these real but potentially controllable problems.