1 History of ?-Lactam Antibiotics.- A. The Past Fifty Years.- I. Flemings Discovery.- II. Discovery of the Therapeutic Power of Penicillin in Systemic Infections.- III. Large-Scale Production.- IV. Wartime Interest in Penicillin in Europe and Japan.- V. Isolation, Structure, and Synthesis.- VI. Penicillin-Resistant Bacteria.- VII. 6-Aminopenicillanic Acid and New Penicillins.- VIII. 7-Aminocephalosporanic Acid and the Cephalosporins.- IX. New ?-Lactam Compounds.- X. Biosynthesis.- XI. Mode of Action and Resistance.- B. The Future.- References.- 2 Mode of Action of ?-Lactam Antibiotics A Microbiologists View.- A. Introduction.- I. Mode of Action Studies: Benefits for Basic and Applied Sciences.- II. Mode of Action of Penicillin: A Multilevel Problem.- B. Journey of the Extracellular Antibiotic to the Intracellular Targets.- I. Extracellular Barriers.- II. Barriers in the Bacterial Envelope.- III. The Outer Membrane of Gram-Negative Bacteria.- IV. The End of the Journey: Arrival at the Plasma Membrane.- C. The Biochemical Targets of ?-Lactam Antibiotics.- I. Selective Toxicity of ?-Lactams.- II. Localization of Radioactively Labeled Penicillin in Bacteria.- III. Morphological and Biochemical Effects of Penicillin.- IV. Penicillin-Sensitive Enzymes.- 1. Molecular Basis of Specificity.- 2. Studies with Model Substrates and Model Enzymes.- V. Penicillin-Binding Proteins (PBPs).- 1. Enzymatic Activity of PBPs with Model Substrates.- 2. Penicillin Binding and Inactivation of Enzyme Activity.- 3. Localization of PBPs.- 4. Labeling of PBPs in Live, Growing Bacteria.- 5. Selective Affinity of PBPs for Various ?-Lactams.- 6. Selective Morphological Effects.- VI. Penicillin-Sensitive Enzymes in Cell Wall Synthesis.- 1. Penicillin-Sensitive Enzymes as PBPs.- D. Physiological Consequences of ?-Lactam Inhibition.- I. Search for the Killing Targets.- II. Labeling of PBPs in Live Bacteria.- III. In Vivo Labeling of PBPs in Pneumococci.- IV. Dynamic Experiments with the Labeling l#0