During the past decade there has been a marked increase in resistance of bacteria to antimicrobial agents. Microorganisms have developed the ability to make altered receptors for antimicrobial agents, have prevented agents from reaching their receptors within the bacterial cell, now have enzymes to destroy antibiotics, and have resistant metabolic pathways. Altered penicillin receptors, penicillin-binding proteins, have been found in Streptococcus pneumoniae, Streptococcus faecalis, Staphylococcus aureus, Neisseria gonorrhoeae, Clostridium, and Pseudomonas aeruginosa. Resistance based on decreased entry of drugs has been found for penicillins, cephalosporins, aminoglycosides, and tetracyclines in the Enterobacteriaceae and Pseudomonas aeruginosa. Beta-lactamase resistance has increased significantly being encountered in Neisseria, Haemophilus, Enterobacteriaceae, and Pseudomonas species. Chromosomal inducible beta-lactamases, which function as cephalosporinases, have been a particular problem in Enterobacter and Citrobacter species, and organisms resistant to the third-generation cephalosporins have been isolated from patients. It is clear that beta-lactamases and changes in cell wall permeability will play an extremely important role in the future of the new penicillins and cephalosporins.